Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[K+]>C(OCC)C.O.N1C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:6][CH2:5][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2Br)cc1
Temperature: 18 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A magnetically stirred solution of 2-bromophenethyl alcohol (5.00 g, 24.9 mmol, ex ALDRICH) and 4-methylbenzenesulfonyl chloride (11.20 g, 59.7 mmol) in diethyl ether (50 ml) was cooled to 0° C. (ice-bath) then treated with powdered KOH (3.2 g, 2.4 mole equiv.). The reaction mixture thus obtained was allowed to warm to 18° C., stirred at this temperature for 2.0 h then diluted with water (100 ml). The separated organic phase was washed with water (1×100 ml) then dried (MgSO4), filtered and concentrated under reduced pressure to give a white solid. Since this material contained residual 4-methylbenzenesulfonyl chloride it was dissolved in pyridine (75 ml) and the resulting solution stirred at 18° C. for 0.16 h then diluted with water (500 ml) and extracted with diethyl ether (1×500 ml). The separated organic phase was washed with HCl (1×250 ml of a 5 M aqueous solution) then sodium hydrogen carbonate (1×250 ml of a 0.5 M aqueous solution) before being dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (8.66 g, 98%) as white crystalline masses, m.p. 39-39.5° C. (Found: C, 50.9; H, 4.2; Br, 22.6; S, 8.8. C15H15BrO3S requires C, 50.7; H, 4.3; Br, 22.5; S, 9.0%). nmax (KBr) 1356, 1177, 1021, 980, 962, 895, 812, 769, 752, 665, 557 cm−1. 1H n.m.r. d 7.68, d, J 8.3 Hz, 2H; 7.45, d, J 7.7 Hz, 1H; 7.27, d, J 8.3 Hz, 2H; 7.17, m, 2H; 7.07, m, 1H; 4.25, t, J 7.0 Hz, 2H; 3.09, t, J 7.0 Hz, 2H; 2.43, s, 3H. 13C n.m.r. d 144.5 (C), 135.3 (C), 132.7 (CH), 132.8 (C), 131.3 (CH), 129.7 (CH), 128.5 (CH), 127.6 (CH), 127.4 (CH), 124.2 (C), 68.6 (CH2), 35.5 (CH2), 21.5 (CH3). Mass spectrum m/z 356 (0.7%) 354 (0.7) (M+.); 184 (98) 182 (100) [M—H3CC6H4SO3H)+.]; 171 (49) 169 (51); 155 (45); 103 (32); 91 (80) (C7H7+).
Reaction SMILES: C[Si](C)(C)Br.[CH2:6]([O:8][C:9](=[O:28])[CH:10]([NH:25]C=O)/[CH:11]=[C:12](\[CH3:24])/[CH2:13][P:14]([O:20]C(C)C)([O:16]C(C)C)=[O:15])[CH3:7].C(O)C>ClCCl>[CH2:6]([O:8][C:9](=[O:28])[CH:10]([NH2:25])/[CH:11]=[C:12](\[CH3:24])/[CH2:13][P:14]([OH:16])([OH:20])=[O:15])[CH3:7]
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
56.7 ml of trimethylbromosilane are added dropwise within a period of 15 minutes at 20° to a solution of 25.42 g of E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 102 ml of dry dichloromethane. After stirring at room temperature for 20 hours, 102 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hours. The clear reaction solution is then completely concentrated by evaporation in vacuo. The residue is concentrated by evaporation a further three times in each case after the addition of 100 ml of toluene. The oily residue is dissolved in 102 ml of ethanol, and a solution of 102 ml of propylene oxide in 102 ml of ethanol is added dropwise thereto. The product, obtained in crystalline form, is filtered off after 2 hours (room temperature) and washed with ethanol and ether. After drying (80°, 4 hours) under a high vacuum, E-2-amino-4-methyl-5 -phosphono-3-pentenoic acid ethyl ester is obtained in analytically pure form, m.p. 212° (decomp.).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:14])[C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[CH3:14][N:5]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[N:4]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1ncc(I)c1Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc(B(O)O)c1Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Iodo-1-methyl-5-phenoxy-1H-pyrazole (862 mg; 2.75 mmol) is dissolved in 15 ml THF extra dry and cooled down to −78° C. Afterwards n-BuLi (1.80 ml; 2.88 mmol; 1.6 mol/l in Hexane) and Triisopropyl borate (982.28 mg; 5.22 mmol) are added. It is stirred for 1 hour. The reaction mixture is quenched with 1 ml water and purified with reversed phase chromatography under basic conditions.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(N2CCOCC2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 4-morpholinoacetophenone (4.61 g, 22 mmol), sulfur (2.16 g, 67 mmol), and morpholine (6 mL, 67 mmol) was heated at 80° C. for 1h then heated under reflux for 18 h. The hot reaction mixture was poured into warm ethanol. Upon cooling to 25° C., a precipitate formed. The precipitate was filtered to provide a tan solid (4.16 g). This crude tan solid was then treated with concentrated acetic acid (16 mL), concentrated sulfuric acid (2.4 mL), and water (3.6 mL). The resulting reaction mixture was heated under reflux for 4 h and then poured into water. The water was removed in vacuo to provide crude (4-morpholin-4-yl-phenyl)-acetic acid as a brown oil (8.20 g). This crude (4-morpholin-4-yl-phenyl)-acetic acid was dissolved in methanol (100 mL) and then slowly treated with concentrated sulfuric acid (1 mL). The reaction mixture was heated under reflux for 66 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with water (200 mL) and then treated with a 10% aqueous sodium hydroxide solution until pH=9. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution) afforded (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (2.22 g, 42% for 3 steps) as a yellow oil: EI-HRMS m/e calcd for C13H17NO3 (M+) 235.1208, found 235.1214.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+].O>C1COCC1.CO>[C:21]([C:19]1[N:20]=[C:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:29])=[O:2])=[CH:8][C:9]=2[C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[O:15])[NH:17][CH:18]=1)#[N:22]
Reactant: COC(=O)C(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 2-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-2-methyl-propionic acid methyl ester (as prepared in the previous step, 60.0 mg, 0.153 mmol) in 1 mL of 1:1 THF/MeOH was added 6 N NaOH (250 μL, 1.50 mmol). After stirring at RT for 18 h, the mixture was treated with 10 mL of H2O and washed with EtOAc (3×10 mL). The aqueous layer was acidified to a pH of 6 with 1 N aqueous HCl and extracted with 10:1 EtOAc-MeOH (3×10 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). The organic solvent was evaporated in vacuo to give the title compound (48 mg, 83%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.19 (m, 1H), 7.90 (s, 1H), 7.31 (m, 1H), 7.20 (s, 1H), 5.84 (m, 1H), 2.17-2.40 (m, 4H), 1.76-1.92 (m, 4H), 1.57 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O3, 379.2 (M+H). found 379.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][C:13]([OH:15])=O)=[CH:3]1.C1(=O)O[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C([O-])(=O)C.[Na+]>O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:12]=[C:13]2\[O:15][C:19](=[O:20])[C:18]3[C:22]\2=[CH:23][CH:24]=[CH:25][CH:17]=3)=[CH:3]1
Reactant: Cc1cccc2c1c(CC(=O)O)cn2C
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c1c(/C=C1\OC(=O)c3ccccc31)cn2C
Temperature: 200 °C

Procedure:
A reaction flask equipped with a nitrogen line and a stir bar is charged with (1,4-Dimethyl-1H-indol-3-yl)-acetic acid (0.5 g, 2.4 mmol) (from example 1.5), 0.3 g (2.4 mmol) of phthalic anhydride followed by 1.2 g (15.2 mmol) of anhydrous sodium acetate. The flask is heated to 200° C. under a stream of nitrogen for 2 h. Water formed is azeotropically evaporated using toluene. The resulting brown melt 11.1 (98%) is taken immediately to the next step LC/MS (M++1): 290.3.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:57])[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:56])[C@@H:16]([NH:30][C:31](=[O:55])[C@H:32]([CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47]CC1C=CC=CC=1)=[O:46])[NH:33]C(OC(C)(C)C)=O)[CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])C1C=CC=CC=1.O1[CH2:63][CH2:62]OCC1>>[ClH:1].[CH2:23]([N:44]([CH2:43][CH2:42][CH2:41][C@H:32]([NH2:33])[C:31](=[O:55])[NH:30][C@@H:16]([CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:15](=[O:56])[NH:14][CH2:13][CH2:12][NH:11][C:10](=[O:57])[O:9][CH2:2][C:63]1[CH:62]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:45](=[O:46])[OH:47])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Product: N[C@@H](CCCN(Cc1ccccc1)C(=O)O)C(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
3.7 ml of a 4M solution of hydrogen chloride in dioxane are added to a solution of 71 mg (0.091 mmol) of benzyl{2-[((2S)-4-{[(benzyloxy)carbonyl]amino}-2-{[N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl]amino}butanoyl)amino]ethyl}carbamate (Example 112A) in 1.5 ml of dioxane at RT. After 4 h at RT, the reaction solution is concentrated in vacuo, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH2:21])=[CH:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chloro-5-fluorophenyl)-quinolin-3-yl)methanamine (0.050 g, 0.156 mmol), 6-chloropurine (0.027 g, 0.17 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=71 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.30 (s, 1 H), 8.20 (s, 1 H), 7.80 (dd, J=7.58, 0.49 Hz, 2 H), 7.69-7.75 (m, 1 H), 7.42-7.47 (m, 1 H), 7.31-7.37 (m, 1 H), 7.11-7.16 (m, 1 H), 6.99-7.06 (m, 1 H), 4.90-497. (m, 2 H), Mass Spectrum (ESI) m/e=440 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21]2)=[O:6]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: c1ccc2c(c1)CCCO2
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL, 4.59 mmol) at 0° C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, and the crude product was dissolved in DCM (4 mL) and added to chroman (488 mg, 3.67 mmol) which had been cooled to 0° C. To this mixture was added aluminum chloride (488 mg, 3.67 mmol) in portions. After stirring for 4 h, the reaction was quenched by pouring it into crushed ice. This was extracted with dichloromethane (50 mL×2). The dichloromethane layers were combined and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL×2), and brine (20 mL), then dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to furnish (2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g).
Reaction SMILES: C1(S([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:25]([OH:46])[CH2:26][N:27]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:39]([N:27]([CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[CH2:26][CH:25]([OH:46])[CH2:24][O:23][C:18]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:22]=2[CH:21]=[CH:20][CH:19]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2c1c1ccccc1n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
3.3 g of 1-(9-Benzenesulfonyl-9H-carbazol-4-yloxy)-3-{benzyl-[2-(2-methoxyphenoxy)-ethyl]-amino}-propan-2-ol (5.2 mmol) were dissolved in 33 ml THF/methanol (2:1). A solution of 1.1 g of sodium hydroxide in 1.7 ml of water was added in one portion. The mixture was stirred for 18 h at 50° C. The mixture was rotary evaporated (35° C./20 mbar). The residue was dissolved in 25 ml of toluene and 20 ml of water. The phases were separated and the toluene phase was washed 3 times with 25 ml of water. The organic phase was rotary evaporated (40° C./15 mbar) and the residue was crystallized with 9 ml ethanol. The product was filtered under suction and washed twice with 3 ml cold ethanol. The substance was dried at 50° C. for 12 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:13][CH:14]=[O:15])[CH3:12].C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:18]([F:21])([F:20])[CH:14]([OH:15])[CH2:13][C:5]1([CH3:12])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1(CC=O)CCOc2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(CC(O)C(F)(F)F)CCOc2ccc(F)cc21
Reaction time: 1 h
Yield: 105.7 %

Procedure:
To 1.7 g (8.16 mmol) of (6-fluoro-4-methylchroman-4-yl)acetaldehyde and 1.69 mL (11.43 mmol) of trimethyl(trifluoromethyl)silane in 15 mL of tetrahydrofuran was added 1 mL (1 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture stirred for 1 hour and then an additional 9 mL (9 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. After 18 hours, the mixture was concentrated in vacuo and diluted with 1 N aqueous HCl and extracted with three 50 mL portions of diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2.4 g of crude 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-ol as a mixture of diastereomers. The crude oil was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@@H:10](O)[CH3:11])=[CH:2]1.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]([N:27]=[N+:28]=[N-:29])[CH3:11])=[CH:2]1
Reactant: C[C@H](O)c1csc2ccccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@@H](N=[N+]=[N-])c1csc2ccccc12
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
The process was carried out with reference to a method of Thompson, et al. (J. Org. Chem. 1993, 58, 5886). Under an argon atmosphere, a mixture of 5.50 g of (1S)-1-(1-benzothiene-3-yl)ethanol and 7.98 g of DPPA was dissolved in toluene, and 5.54 mL of DBU was then added thereto in an ice bath. After stirring for 30 min under ice-cooling, it was further stirred at room temperature for 15 hours. The reaction mixture was washed with water and 1 M hydrochloric acid in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5.86 g of (1R)-1-(1-benzothiene-3-yl)ethylazide as a colorless oily substance. EI: 203
Reaction SMILES: C1C[O:4][CH2:3]C1.[C:6]([Si:10]([O:13][C:14]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C([Li])(CC)C.[Cl-].[NH4+]>C(OCC)C.CN(C=O)C>[Si:10]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[CH:3]=[O:4])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
A 250 ml THF solution containing 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 7.74 ml of DMF, the mixture was stirred at −75° C. for 1 hour and the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride solution were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (12.6 g) as a colorless solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([C@@H:12]1[CH2:16][O:15][C:14](=[O:17])[N:13]1[C:18](=[O:26])/[CH:19]=[CH:20]/[CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:27]N1C(=O)CCC1=O>C1COCC1.CSC>[CH2:5]([C@@H:12]1[CH2:16][O:15][C:14](=[O:17])[N:13]1[C:18](=[O:26])[C@H:19]([Br:27])[C@@H:20]([CH2:1][CH3:2])[CH2:21][C:22]([F:23])([F:24])[F:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(/C=C/CC(F)(F)F)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CSC
Product: CC[C@@H](CC(F)(F)F)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -15 °C
Reaction time: 0.67 h
Yield: 59.4 %

Procedure:
A slurry of copper bromide (I)-dimethyl sulfide complex (1.57 g, 7.66 mmol) in THF (20 mL) and dimethyl sulfide (10 mL) as co-solvent was cooled to −40° C. and ethyl magnesium bromide (5 mL, 15.3 mmol) was added dropwise for 10 min. The slurry was stirred for 40 min while warming to −15° C. The greenish slurry was cooled to −40° C. and (4R)-4-benzyl-3-[(2E)-5,5,5-trifluoropent-2-enoyl]1,3-oxazolidin-2-one (2 g, 6.38 mmol) was added dropwise as a solution in THF (5 mL) at 40° C. The reaction was allowed to warm to 25° C. overnight (20 h). The black slurry was cooled down to −78° C. and N-bromosuccinimide (2.3 g 12.76 mmol) was added portionwise. It was allowed to warm to −40° C. and stirred for an additional 30 min. After this period, the black slurry became greenish to blue. A precipitate formed and was filtered off. The mother liquor was diluted with EtOAc (150 mL) and the organic layer was washed with saturated NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford (4R)-4-benzyl-3-[(2R,3S)-2-bromo-3-ethyl-5,5,5-trifluoropentanoyl]-1,3-oxazolidin-2-one as a green semi-solid (1.6 g, 59.5%). Mass Spectrum (−ESI): 421, 420 (M−H)−.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1
Reactant: Cn1nnc2c3nc(O)c(O)nc3ccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c3nc(O)c(O)nc3cc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 82.9 %

Procedure:
Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6 mmol) in 20 ml of conc. sulfuric acid at 0° C. After 1 h the ice bath was removed and the mixture was stirred over night at room temperature. Then an additional amount of potassium nitrate (0.47 g) was added and stirring was continued over night at room temperature. The solution was poured into ice/water and the precipitated solid was collected, washed with water, and dried to give 1.0 g (83%) of the pure nitro compound; m.p.>300° C.; IR (KBr): 1710 cm-1 ; 1H-NMR (DMSO-d6): 4.50 (s, 3H, CH3), 8.18 (s, 1H, ArH), 12.13 (broad s, 1H, OH), 13.17 (broad s, 1H, OH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:24].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (7.1 g) in N,N-dimethylformamide (71 ml) was added 60% sodium hydride in mineral oil (1.13 g) under ice-cooling, and stirred for 1 hour at ambient temperature. The suspension was then stirred for 1.5 hours at 60° C. To the reaction mixture was added iodomethane (32 ml) at 40° C., and stirred for 30 minutes at 45° C. Water and ethyl acetate were added with stirring, and the organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using n-hexane/ethyl acetate (4:1) as the elution to give 4-methoxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (6.63 g).