Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br-].[K+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.1 %

Procedure:
A slurry of 41.7 g (0.3 mol) of o-nitrophenol in 200 ml of ethanol was added to a stirred, cooled solution of 19.8 g (0.3 mol) of 85% potassium hydroxide in 300 ml of ethanol; a voluminous yellow-orange precipitate of the potassium salt separated. After stirring at room temperature for 45 minutes, a solution of 35.7 ml (0.3 mol) of benzyl bromide in 100 ml of ethanol was added portionwise (no temperature rise) and the mixture was stirred at room temperature for 30 minutes, then gradually heated to reflux. The solid went into solution as the color lightened from red to light yellow and potassium bromide separated. After refluxing for 3 hours, the mixture was cooled and most of the ethanol removed on a rotary evaporator. The residue was shaken with 300 ml of ether and 100 ml of water and the layers separated. The aqueous phase was extracted with ether (2×100 ml) and the combined ether layers were washed with 50 ml of water and 50 ml of saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was evaporated to give 66.1 g of a red-orange oil which was fractionated to yield 44.3 g of the title A compound as a yellow oily product, b.p. 163°-166° (0.2 mm). Lit. b.p. 127°-129° (0.05 mm); J. Org. Chem., 37, 1848 (1972).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][O:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[H-].[Na+].[Na].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl>>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C@H:2]1[CH2:3][O:4][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH2:7]1
Reactant: Fc1ccccc1CCl
Reactant: O[C@H]1CO[C@@H](c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: Fc1ccccc1CO[C@H]1CO[C@@H](c2ccccc2)OC1

Procedure:
Using the method of Example 8, cis-5-hydroxy-2-phenyl-1,3-dioxane (8.4 g, 0.047 mole) was reacted with sodium hydride (2.0 g of 61%, 0.047 mole). The reactant sodium salt was reacted with 2-fluorobenzyl chloride (7.2 g, 0.05 mole) to give, after recrystallization from benzene-ligroin, 2.8 g of white solid, m.p. 65°-67° C, and on further recrystallization, a solid, m.p. 70°-71° C. Analysis by VPC indicated the product to be 90% cis-5-(2-fluorobenzyloxy)-2-phenyl-1,3-dioxane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)#[N:32]>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cc3)c2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation TT) and 4-cyanophenylacetic acid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([NH:10]C(OC(C)(C)C)=O)[CH:7]=[CH:6]1)=[N+:2]=[N-:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([NH2:10])[CH:7]=[CH:6]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NC1C=CC(CN=[N+]=[N-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCC1C=CC(N)C1
Yield: 79.3 %

Procedure:
N-[4-(azidomethyl)cyclopent-2-enyl](t-butoxy)-carboxamide (10 g, 42 mmol) was dissolved in TFA reagent (9.25 mL TFA, 0.25 mL anisole, 0.25 mL triisopropylsilane and 0.25 mL water)and DCM (25 mL), and stirred for 30 min at rt. The reaction mixture was concentrated and the residue filtered through SCX column, eluted with ammonia (2 M solution in methanol), and evaporated to yield the title compound (4.6 g, 80%).: ESMS: 139 (M+1)+. 1H NMR (CDCl3): δ 1.40-1.55 (m, 1H), 2.45-2.60 (m, 1H), 2.90-3.00 (m, 1H), 3.40 (d, 2H), 4.104.20 (m, 1H), 5.90 (s, 2H).
Reaction SMILES: O[C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl>[O:6]1[C:5]2([CH2:10][CH2:11][C:2]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)=[CH:3][CH2:4]2)[O:9][CH2:8][CH2:7]1
Reactant: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of 4-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (7.8 g) in methylene chloride (100 mL) was added triethylamine (21 mL) at room temperature. The solution was cooled down to −40° C. and then mesyl chloride (4.7 mL) was added dropwise. The reaction mixture was stirred at 40° C. for 30 min, then warmed up to room temperature gradually and continuously stirred overnight. The reaction was quenched with sat. aqueous NaHCO3 solution. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine, dried with Na2SO4, then evaporated. The residue was purified by column (Hex/EtOAc=5/1) to give the product 5.2 g as a white solid (yield: 71%): 1H NMR (CDCl3) δ 7.62-7.55 (2H, m), 7.50-7.45 (2H, m), 6.17-6.13 (1H, m), 4.02 (4H, s), 2.68-2.62 (2H, m), 2.53-2.47 (2H, m), 1.96-1.92 (2H, m); MS: 242 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]5[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=5[CH:40]=4)=[O:29])[CH2:23][CH2:22]3)=[N:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:7][C:8]1[CH:17]=[C:16]2[C:11](=[CH:10][CH:9]=1)[N:12]=[CH:13][C:14]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([NH:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]4[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=4[CH:40]=3)=[O:29])[CH2:25][CH2:26]1)=[N:15]2
Reactant: COC(=O)CBr
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.9 %

Procedure:
Bromo-acetic acid methyl ester (20.0 μL, 0.22 mmol, 1.05 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (100 mg, 0.21 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by potassium carbonate (57.6 mg, 0.42 mmol, 2.0 eq). After 5 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford [3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yloxy]-acetic acid methyl ester as a white powder (8 mg, 6% yield).
Reaction SMILES: [CH3:1][NH2:2].CO.C(OC([NH:12][C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[C:15]([C:22]([O:24]CC)=O)[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:12][C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[C:15]([C:22]([NH:2][CH3:1])=[O:24])[CH:14]=1
Reactant: CN
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c2ccsc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNC(=O)c1cc(N)c2ccsc2c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A 40% methylamine-methanol solution (3 ml) was added to ethyl 4-(tert-butoxycarbonylamino)benzo[b]thiophene-6-carboxylate obtained in Example 22 (Step 3) (110 mg), and the reaction solution was stirred at 90° C. overnight. Trifluoroacetic acid (0.5 ml) was added to the resultant residue, and the reaction solution was stirred at room temperature for 15 minutes. Thereafter, the solvent was evaporated under vacuum, and the residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 4-amino-N-methylbenzo[b]thiophene-6-carboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 3-(3-cyanophenylsulfonyloxy)-5-methylphenol (2.30 g, 8.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (2.4 g, 12.0 mmol) and 1,3-propanediol (3.0 g, 40 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (3.0 g, 12.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (100 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (10% ethyl acetate in dichloromethane) to give the title compound as a colorless oil (2.2 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 6.65 (s, 1H), 6.40 (s, 1H), 6.37 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 2.00 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:30])[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[CH2:13][CH2:12][CH2:11]2.[ClH:31]>CO>[ClH:31].[ClH:31].[NH:20]1[CH2:21][CH2:22][CH:18]([N:14]2[C:15]3[C:10](=[CH:9][C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:30])=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)CCCN2C1CCNC1)c1cccs1
Temperature: 90 °C

Procedure:
A solution of tert-butyl 3-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (Isomer 2) (520 mg, 1.219 mmol) in MeOH (26 ml) was treated with 3N HCl (4.06 ml, 12.19 mmol) then heated at 90° C. for 30 minutes. After cooling, the mixture was concentrated to dryness and dried under reduced pressure overnight. The solid was triturated with 5% isopropanol/95% hexanes (50 mL), collected and dried under reduced pressure (391 mg, 80%). ESI-MS (m/z, %) 327.2 (MH+, 90%), 258.1 (100%); ESI-HRMS calculated for C18H23N4S (MH+), Calculated: 327.1637; Observed: 326.1635; Chemical purity: 97.3%; Optical Rotation: 25[α]589=+0.19°, c=0.95 in methanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27]O>>[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: COCCCCO
Product: COCCCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 58 with 4-methoxybutanol gave 2-(3-(3-(4-methoxybutoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.840 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.85 (m, 2H), 7.68-7.72 (m, 2H), 7.11-7.17 (m, 1H), 6.72-6.79 (m, 2H), 6.65 (dd, J=8.2, 2.4 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 3.75 (t, J=6.8 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 3.35 (s, 3H), 2.65 (t, J=7.2 Hz, 2H), 1.98-2.06 (m, 2H), 1.70-1.86 (m, 4H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([NH:22][CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[N:28]([CH:34]2[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]2=[O:41])[CH2:27]3)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:42])=[O:11])=O)(C)(C)C.[ClH:43]>C(Cl)Cl.CCOCC>[ClH:43].[NH2:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([NH:22][CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[N:28]([CH:34]2[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]2=[O:41])[CH2:27]3)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:42])=[O:11]
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN
Reaction time: 24 h

Procedure:
To a mixture of 5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenyl 2-(tert-butoxycarbonylamino)acetate (0.58 g, 1.0 mmol) in DCM (50 mL) is added 2M HCl in ether (1 mL), and the mixture is stirred for 24 hrs. The solid precipitate is filtered, rinsed with DCM (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([F:12])[F:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([F:11])[F:12])=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Yield: 83.4 %

Procedure:
Diethyl [(4-nitrophenyl)(difluoro)methyl]phosphonate (Compound 188B, 267 mg) was hydrogenated in the presence of 10% Pd/C (30 mg) in MeOH (10 mL) under 1 atmosphere for 4 h. The catalyst was filtered off, the filtrate was concentrated, and the residue was purified by silica gel chromatography (2% MeOH in DCM) to afford 201 mg of the desired product (yield: 83%). 1H NMR (CDCl3, 400 MHz): δ=1.35 (t, J=7.6 Hz, 6 H), 4.08 (s, br, 2 H), 4.31 (q, J=7.6 Hz, 4 H), 6.64 (d, J=8.8 Hz, 2 H), 7.86 (d, J=8.0 Hz, 2 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:17]1[S:21](=O)[CH2:20][CH2:19][CH2:18]1.C(OC(C)C)(C)C.[C:30]([O:38][CH:39]([C:47]([F:50])([F:49])[F:48])[C:40]([F:46])([F:45])[S:41]([O-:44])(=[O:43])=[O:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>[C:30]([O:38][CH:39]([C:47]([F:49])([F:50])[F:48])[C:40]([F:45])([F:46])[S:41]([O-:44])(=[O:43])=[O:42])(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1.[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S+:21]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)COc1cccc2ccccc12
Reactant: O=S1CCCC1
Agent: CS(=O)(=O)O
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CC(C)OC(C)C
Product: FC(F)(F)COc1ccc([S+]2CCCC2)c2ccccc12
Reaction time: 8 h

Procedure:
In 6 g of Eaton's reagent (Aldrich, diphosphorus pentoxide/methanesulfonic acid solution) was dispersed 2.4 g (0.0107 mol) of 1-(2,2,2-trifluoroethoxy)naphthalene in Synthesis Example 1-3. With stirring, 2.2 g (0.0214 mol) of tetramethylene sulfoxide was added dropwise to the dispersion. The solution was matured overnight at room temperature and combined with 30 g of water and 30 g of diisopropyl ether, from which a water layer was separated. The water layer was again washed with 30 g of diisopropyl ether. This aqueous solution was combined with 3.4 g (0.0095 mol) of sodium 2-benzoyloxy-1,1,3,3,3-pentafluoropropanesulfonate synthesized in accordance with the teaching of JP-A 2007-145797, after which extraction was effected twice with 50 g of dichloromethane. The organic layer was washed with water and distilled in vacuum to remove the solvent. The residue was poured into isopropyl ether for crystallization, filtered and dried, obtaining the target compound. White crystals, 5.3 g, yield 87%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16]O)([O-:3])=[O:2].S(Cl)([Cl:20])=O>ClC(Cl)Cl>[Cl:20][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 12.5 parts of 2-{[2-nitro-4-(trifluoromethyl)phenyl]amino}ethanol and 150 parts of trichloromethane are added dropwise 7.5 parts of sulfinyl chloride. Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding N-(2-chloroethyl)-2-nitro-4-(trifluoromethyl)benzenamine.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15])([O-:7])=[O:6]>C(Cl)Cl>[CH:1]1([NH:4][S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N+:5]([O-:7])=[O:6])(=[O:15])=[O:16])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a −78° C. mixture of cyclopropylamine (10 g, 1.75 mmol) in CH2Cl2 (100 mL) was added a solution of 2-nitrobenzene sulfonyl chloride (22.1 g, 85.7 mmol) and the mixture was stirred for 12 h. The mixture was washed with 1N HCl dried over MgSO4 then concentrated to give 18.7 g, (88%) of a N-Cyclopropyl-2-nitro-benzenesulfonamide as a tan solid.
Reaction SMILES: FC(F)(F)C(N[C@@H:6]1[C:14]2C(=CC=C(OC)C=2)C(=O)[CH2:7]1)=O.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].IC(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:6]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25])([CH3:14])[CH3:7]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 24 h
Yield: 85 %

Procedure:
Step AU (1). A solution of 3-hydroxybenzaldehyde (67 g, 549 mmol), 2-iodopropane (100 g, 588 mmol) and K2CO3 (130 g, 942 mmol) in 400 mL DMF was stirred for 18 h. To the above solution was added 2-iodopropane (20 g, 117 mmol) and K2CO3 (20 g, 145 mmol) and the mixture was stirred for another 24 h. The reaction mixture was poured into 300 mL water which was extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (100 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo to afford 77 g (85% yield) of 3-isopropoxybenzaldehyde as an oil. 1H NMR (300 MHz, CDCl3) δ 1.29-1.31 (d, 6H) 4.5-4.6 (m, 1H) 7.0-7.1 (m, 1H) 7.3-7.4 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:10]([NH:15][C:16]([C@H:18]1[O:20][C@@H:19]1[C:21]([OH:23])=[O:22])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:24][CH:25](O)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C@@H:3]([C@@H:10]([NH:15][C:16]([C@H:18]1[O:20][C@@H:19]1[C:21]([O:23][CH:25]([CH3:26])[CH3:24])=[O:22])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)O
Reactant: CO[C@H](c1ccccc1)[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@H](c1ccccc1)[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)OC(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,3S)-3-[[1-(S)-[α-(R)-methoxybenzyl]-3-methylbutyl]carbamoyl]oxirane-2-carboxylic acid (105 mg, 0.327 mmol), 2-propanol (30 μl, 0.40 mmol.) and 4-dimethylaminopyridine (8 mg, 0.07 mmol.) in anhydrous dichloromethane (4 mL) was added 1,3-dicyclohexylcarbodiimide (75 mg, 0.36 mmol.) under chilling with ice. The resulting mixture was stirred at 5° C. for 30 minutes, and then stirred overnight at room temperature. The mixture was placed under reduced pressure to distill off the solvent. The residue was mixed with ethyl acetate and 10% citric acid, and the insoluble material was removed by filtration. The filtrate was successively washed with water, aqueous saturated sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by middle pressure silica gel column chromatography (n-hexane/ethyl acetate=3/1), to give the titled compound as a white crystalline product (70 mg, yield: 59%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:70]1[C:75]([CH3:76])=[CH:74][CH:73]=[CH:72][C:71]=1[C:77]1[O:78][CH:79]=[C:80]([CH3:82])[N:81]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:76][C:75]1[CH:74]=[CH:73][CH:72]=[C:71]([C:77]2[O:78][CH:79]=[C:80]([CH3:82])[N:81]=2)[C:70]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:26])[C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[CH:16]2
Reactant: Cc1coc(-c2cccc(C)c2Br)n1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1coc(-c2cccc(C)c2-c2ccc3nc(N)c(N4CCOCC4)cc3c2)n1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.055 g, 0.155 mmol, prepared as in Example 2, Step 1-2), potassium phosphate (0.131 g, 0.619 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.015 g, 0.031 mmol), Pd2(dba)3 (7.09 mg, 7.74 μmol), and 2-(2-bromo-3-methylphenyl)-4-methyloxazole (0.078 g, 0.310 mmol). The vessel was evacuated and flushed with nitrogen three times before dioxane (1.0 mL) and water (0.50 mL) (each degassed by bubbling nitrogen gas through the solution for 10 min prior to addition) were added. The reaction mixture was stirred and heated in a microwave at 130° C. for 15 min. The reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide and extracted with EtOAc. The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography by eluting with 1:15:15 2M NH3 in MeOH/DCM/diethyl ether to provide the desired product which after triturating with diethyl ether gave 6-(2-methyl-6-(4-methyloxazol-2-yl)phenyl)-3-morpholinoquinolin-2-amine as white solid. MS (ESI, pos. ion) m/z: 401 (M+1).