Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].I[CH2:15][CH2:16][C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18].O>C1COCC1>[Si:20]([O:19][C@H:17]([CH3:18])[CH2:16][CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22]
Reactant: C[C@H](CCI)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC[C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g of diethyl malonate in 5 ml of THF was added dropwise into a suspension of 0.05 g of sodium hydride in THF. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and a solution of 0.65 g of (R)-1-iodo-3-t-butyldimethylsilyloxybutane in THF was added to the mixture. Then, the mixture was stirred at room temperature overnight, water was added to the mixture, and the majority of THF was removed by distillation. The residue was extracted with ether, and the ether extract was washed with dilute hydrochloric acid and then with water and dried over magnesium sulfate. The solvent was removed by distillation and the residue was subjected to distillation under a reduced pressure to obtain diethyl (R)-3-t-butyldimethylsilyloxybutylmalonate. The obtained compound was dissolved in 10 ml of THF and 2 ml of a 1M solution of tetrabutyl ammonium fluoride in THF was added to the solution, and the mixture was stirred at room temperature overnight and concentrated under a reduced pressure. Water was added to the concentrate and the mixture was extracted with ether. The ether extract was washed with water and dried over magnesium sulfate. Ether was removed by distillation, the residue was dissolved in benzene, p-TsOH was added to the solution and the mixture was refluxed for 5 hours. The reacted solution was washed with an aqueous solution of sodium hydrogen carbonate and dried, the solvent was removed by distillation, and the residue was purified by the silica gel column chromatography to obtain (2RS,5R)-2-ethoxycarbonyl-5-methyl-δ-valerolactone. The obtained compound was reduced with sodium borohydride to obtain (2RS,5R)-2-hydroxymethyl-5-methyl-δ-valerolactone. In the same manner as described in Example 1, the obtained compound was reacted with 4-(4'-octyloxy)biphenol by using triphenylphosphine and diethyl azodicarboxylate. The reacted solution was purified by the silica gel column chromatography to obtain (2RS,5R)-2-(4'-octyloxybiphenyl)oxymethyl-5-methyl-δ-valerolactone. The obtained product was further fractionated and purified by HPLC to obtain (2R,5R)-2-(4'-octyloxybiphenyl)oxymethyl-5-methyl-δ-valerolactone and (2S,5R)-2-(4'-octyloxybiphenyl)-oxymethyl-5-methyl-δ-valerolactone. They showed the following phase transitions. ##STR39##
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.BrC[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][O:16]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: BrCCC1CCOCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(Cl)c2ncn(CC3CCOCO3)c2n1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Equimolar amounts of 2-amino-6-chloropurine, 4-bromoethyl-1,3-dioxane (prepared according to Price C. C. J. Amer. Chem. Soc. 1950, 72, 5335-6) and anhydrous potassium carbonate were mixed in dry dimethyl formamide. After stirring for seven days at room temperature the mixture was filtered and the filtrate evaporated at reduced pressure. The residue was triturated with hot ethanol and undissolved material filtered off. The filtrate was evaporated to dryness and a yellow crystalline solid was obtained which was recrystallized from chloroform to give colourless rod-shaped crystalls. M.p. 169°-70° C. (uncorr.) UV Spectra (hydrochloric acid 0.01 mol/l): λmax (nm) 308, 245. UV spectra (ethanol): λmax (nm) 310, 247. M.S.: 11.2 a J., m/e (int): 271/269 (0.19/0.55), 226/224 (0.11/0.28) 212/210 (0.38/0.82) 171/169 (0.35/1.0)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CC(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.10 g, 0.28 mmol) and triethylamine (0.1 mL, 0.66 mmol) were combined in CH2Cl2 (2 mL). Isovaleryl chloride (0.04 mL, 0.33 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After aqueous workup, the crude material was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]3OCC[O:19]3)=[CH:14][CH:13]=1)=[N:7]2>O1CCOCC1>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=1)=[N:7]2
Reactant: Clc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
To a solution of 3-3 (5.0 g, 12.9 mmol) in 1,4-dioxane (30 mL) at 0° C. was added 8.5 mL of 3NHCl (25.7 mmol). The mixture was allowed to warm up to room temperature and stirred for 1.3 hr. The reaction was quenched by NaHCO3 (sat) until pF=7-8. The mixture was extracted by EtOAc (×3). The combined organic layers was washed with brine and dried over MgSO4 and concentrated to afford a yellow solid as the desired product A. LC/MS found: M+1=345.1
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Br[C:15]1[N:16]=[C:17]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[S:18][CH:19]=1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([O:20][C:17]2[S:18][CH:19]=[C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)[N:16]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(S(C)(=O)=O)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate 21) and tert-butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46) (0.007 g, 5%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.[Al].O>CN(C=O)C>[Br:23][C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:14](=[O:15])[NH:13][CH:12]=1
Reactant: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (46 g, 228 mmol) in DMF (370 mL) was added NBS (44.5 g, 250 mmol) in small portions at 0° C. The reaction mixture was covered with aluminum foil and left to stir at room temperature overnight. The reaction mixture was treated with water (460 mL), left to stir for 3 h, filtered, and washed with water. The cake was dissolved in MeOH and filtered to remove residual solids. The filtrate was treated with charcoal, and warmed to 40° C. for 2 h. The mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The residue was treated with isopropanol and heptane, filtered, and washed with MTBE to afford the title compound as the isopropanol solvate. 1H NMR (600 MHz, CD3SOCD3) 3 12.03 (s, 1H); 11.47 (s, 1H); 7.71 (dd, 1H); 7.59 (s, 1H); 7.52 (dd, 1H); 7.17 (dt, 1H). LRMS (APCI) calc'd for (C11H6BrFN2O) [M+H]+, 281.0. found 280.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5]([O:7][CH3:23])=[O:6]
Reactant: Cc1ccc(Sc2ccccc2)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1Sc1ccccc1

Procedure:
650 g of 3-methyl-6-(phenylthio)-benzoic acid in 7.5 litres of absolute methanol are slowly treated with 300 ml of concentrated sulphuric acid and the mixture is heated for 24 hours under reflux. The mixture is concentrated and the residue poured on to an ice-cold sodium bicarbonate solution. The mass is extracted with ether, washed with water, dried over sodium sulphate and concentrated. There is obtained methyl 3-methyl-6-(phenylthio)-benzoate as a red-brown oil which crystallises on standing.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:36])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Cl>C(OCC)(=O)C>[CH3:36][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([N:5]1[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])(=[O:37])[CH2:3][CH2:4]1)[CH:22]=[C:21]2[O:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(OC3CCN(C(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(OC3CCNC3)c2c1
Yield: 45.3 %

Procedure:
A mixture of tert-butyl 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}pyrrolidine-1-carboxylate (50 mg, 0.096 mmol) and a solution of hydrochloride in ethyl acetate (30 mL, 4 M) was stirred at room temperature for 8 hours. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC and SPE to afford 18.4 mg of the desired product (yield was 45.3%). MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 8.11-8.08 (d, J=6.4 Hz, 1 H), 7.95-7.88 (m, 2 H), 7.78-7.70 (m, 2 H), 7.68-7.56 (m, 2 H), 6.62 (s, 1 H), 5.75-5.70 (m, 1 H), 5.40 (s, 2 H), 4.70-4.50 (m, 2 H), 3.80-3.70 (m, 4 H), 3.65-3.48 (m, 2 H), 2.60-2.50 (m, 1 H), 2.46 (s, 3 H), 2.46-2.35 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][CH:21]([CH3:30])[CH2:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH:21]([CH3:30])[CH3:20])[CH2:24][CH2:25]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)CN1CCC(=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)CN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 48 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with 1-(2-methylpropyl)-4-piperidone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isobutyl-piperidin-4-yl)-methyl-amine as a solid (48% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 346 as a solid (60% yield). NMR (CDCl3, 400 MHz), 0.91 (6H, d, J=6.6), 1.587-1.70 (2H, m), 1.71-1.79 (3H, m), 1.89 (2H, t, J=11.7), 2.07 (2H, d, J=7.3), 2.37 (3H, s), 2.48-2.54 (1H, m), 2.96 (2H, d, J 11.6), 3.88-3.90 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=497
Reaction SMILES: [C:1]([O:4][C@@:5]1([C:28]#[CH:29])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14]([CH:15]=[C:16]([O:23]CC)[CH2:17][CH2:18]1)=[C:13]([CH:26]=O)[CH2:12]3)(=[O:3])[CH3:2].[BH4-].[Na+].S(=O)(=O)(O)O>C(O)C.CN(C=O)C>[C:1]([O:4][C@@:5]1([C:28]#[CH:29])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[C:13](=[CH2:26])[CH2:12]3)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC(C=O)=C4C=C(OCC)CC[C@@H]4[C@H]3CC[C@@]21C
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 84.4 %

Procedure:
2.8 g of 17beta-acetoxy 3-ethoxy 17alpha-ethynyl 6-formyl 3,5-estradiene, 8.5 ml (abs) ethanol (3.03 vol), 7 ml dimethylformamide (2.5 vol), and 0.13 g sodium borohydride (0.046 p) are introduced under agitation and under a nitrogen atmosphere into a 50 ml three-necked flask. The reaction is stopped after agitation for 22 hours. The reaction medium is hydrolyzed by introducing a solution composed of 2.8 ml (1 vol) of 2N sulphuric acid, 6 ml (2.1 vol) DMF, and 6 ml (2.1 vol) (abs) ethanol over 10 minutes. 2.1 g (yield=84%) of a creamy white product is obtained. M.p.=157° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:29]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)c(F)c21
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.0 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.89 g), DBU (0.62 g) and anhydrous acetonitrile (30 ml) was refluxed for 2 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml), washed with 10% aqueous citric acid solution and water successively, dried over anhydrous sodium sulfate and concentrated. To the resulting residue was added hot methanol to crystallize and then cooled. The resulting precipitate was collected by filtration, added to the mixture of concentrated hydrochloric acid-methanol (1:1, 18 ml) and stirred at room temperature for an hour. The reacting mixture was neutralized with concentrated aqueous ammonia and the resulting precipitate was collected by filtration, washed with ice-water sufficiently and recrystallized from dichloromethane-methanol (1:1) to give the title compound (0.41 g) as colorless prisms, mp 232°-234° C. (decompd.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: Clc1ccc2cc[nH]c2c1
Product: Cc1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-4-methylbenzene: ESMS m/e: 241.9 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:14](O)=[O:15])[C:11](=[O:13])[O:12][C:7]=2[C:6]=1[O:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:14]([Cl:25])=[O:15])[C:11](=[O:13])[O:12][C:7]=2[C:6]=1[O:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)c(=O)oc2c1OC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)c(=O)oc2c1OC(C)=O

Procedure:
A mixture of 7,8-diacetoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (612 mg), thionyl chloride (0.5 mL), dimethylformamide (one drop), and benzene (40 mL) was refluxed for 1 hour and then concentrated to about 10 mL. Hexane (20 mL) was added and the separated precipitates were filtered off, followed by vacuum drying, to yield 7,8-diacetoxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride (600 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([NH2:18])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1)[CH3:2].CCN(CC)CC.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[S:33][C:32]([S:34]([NH:18][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=[CH:7][N:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:36])=[O:35])=[CH:31][CH:30]=1
Reactant: CCC(CC)C(N)c1ncnn1Cc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ncnn1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 60 %

Procedure:
To a stirred solution of the {2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}amine (0.133 g, 0.481 mmol) in CH2Cl2 (10 mL) was added Et3N (0.10 mL, 0.72 mmol) followed by 5-chlorothiophene-2-sulfonyl chloride (0.115 g, 0.529 mmol). The reaction mixture was stirred for 18 h, concentrated in vacuo, partitioned between 0.1N HCl and EtOAc. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 3:7) provided pure material as a yellow solid in 60% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]=O>[F:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:7]=1
Reactant: Fc1cncc(Br)c1
Reactant: c1cn[nH]c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cncc(-n2cccn2)c1
Temperature: 90 °C
Reaction time: 60 h

Procedure:
3-Bromo-5-fluoropyridine (300 mg, 1.705 mmol), 1H-pyrazole (180 mg, 2.64 mmol), ferric acetylacetonate (181 mg, 0.511 mmol), copper(II) oxide (13.6 mg, 0.170 mmol) and cesium carbonate (1.11 g, 3.41 mmol) were suspended in DMF (2.0 mL). The reaction mixture was stirred at 90° C. for 60 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (3×30 mL) and water (100 mL). The organic layers were combined, washed with brine (50 mL) and dried (sodium sulfate). It was then concentrated and the residue was purified by silica gel flash chromatography to afford the titled compound: 1H NMR (400 MHz, methanol-D4) δ ppm 6.55-6.65 (m, 1H), 7.80 (d, J=1.2 Hz, 1H), 8.10 (dt, J=9.9, 2.3 Hz, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.42 (d, J=1.5 Hz, 1H), 8.93 (s, 1H). MS (ESI) m/z=163 (M+H)+. Anal. Calcd. for C8H6FN3.0.15CH3OH: C, 61.99; H, 4.48; N, 32.42. Found: C, 62.30; H, 4.12; N, 32.21.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[N+:17]([C:20]1[CH:21]=[C:22]([NH:26][NH2:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].Cl.C(O)C>O>[N+:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[N:27]2)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (432.3 mg, 2 mmol), 3-nitrophenylhydrazine hydrochloride (379.2 mg, 2 mmol), concentrated hydrochloric acid (0.2 mL) and ethanol (8 mL) was reflued for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→3:1) to give the title compound (631.5 mg, 94.7%) as a light yellowish white powder.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([CH2:8][O:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[O:7])[CH3:4].[C:15](=S)=[S:16].CS(C)=O>C(O)C.O>[CH2:3]([O:5][C:6]([CH2:8][O:9][CH2:10][C:11]1[O:12][C:15]([SH:16])=[N:14][N:13]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)COCC(=O)NN
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)COCc1nnc(S)o1

Procedure:
A solution of potassium hydroxide (0.22 g.) in ethanol (2.5 ml.) was added to a suspension of ethoxycarbonylmethoxyacetohydrazide in ethanol (4 ml.), followed by the addition of carbon disulfide (0.95 ml.) and dimethyl sulfoxide (0.54 ml.), respectively. The reaction mixture was then refluxed for a period of 12 hours, cooled and filtered, and the resulting filtrate subsequently evaporated in vacuo. The residual oil so obtained was then dissolved in water, filtered and the filtrate acidifed to pH 2.0 with aqueous 2N hydrochloric acid. Extraction of the latter solution with ethyl acetate and subsequent evaporation of the solvent then yielded the desired product, viz., 2-(ethoxycarbonylmethoxymethyl)-1,3,4-oxadiazole-5-thiol, as a white solid material (yield, 0.5 g.), m.p. 101°-103° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C@@H:33]([CH3:36])[CH2:34][CH3:35])=[CH:27][CH:26]=1)[C:21](OC)=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[K+]>C(OCC)(=O)C>[OH:22][CH2:21][C@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:13])([CH3:15])[CH3:14])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C@@H:33]([CH3:36])[CH2:34][CH3:35])=[CH:29][CH:30]=1
Reactant: CC[C@H](C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
A room temperature suspension of lithium aluminum hydride (320 mg, 8.5 mmol) and tetrahydrofuran (50 mL) was treated slowly with a solution of (2R)-Methyl 2-(tert-butoxycarbonylamino)-(4-((S)-2-methyl-butoxy)-phenyl)acetate and tetrahydrofuran (40 mL). The resulting reaction mixture was maintained 30 min, and then treated with ethyl acetate (12 mL) and an aqueous solution of potassium hydroxide (10% wt/wt, 24 mL). The mixture was allowed to stir for 1 h, then dried with MgSO4, filtered and concentrated to afford tert-butyl (R)-2-hydroxy-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate (2.2 g, 88% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.12 (d, J=6.3 Hz, 1H), 4.74 (br. s., 1H), 3.80-3.87 (m, 3H), 3.74 (dd, J=9.1, 6.6 Hz, 1H), 1.87 (dq, J=13.0, 6.5 Hz, 1H), 1.53-1.64 (m, 2H), 1.45 (s, 9H), 1.22-1.34 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 0.97 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 324.1 [(M+H)+, calcd for C18H30NO4 324.4].