Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11]([O-:14])([O-])=O.[K+].[K+].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)CCC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][CH2:8][CH2:9][CH2:2][CH2:3][CH3:4])[CH:5]=[O:6])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCCCCCI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Yield: 161 %

Procedure:
3,4-Dihydroxy-benzaldehyde (2.1 g, 0.015 mol), K2CO3 (4.0 g, 0.03 mol) and 1-iodohexane (6.4 g, 0.03 mol) were stirred in 100 ml of 1-butanol under reflux for 24 h. After cooling, the 1-butanol was removed by rotary evaporation. The residue was dissolved in 200 ml of ether, washed with water (dist.) and brine. The solution was dried over Na2SO4 and the solvent was removed to yield 3.7 g 3,4-Bis-hexyloxy-benzaldehyde (85%) as a dark solid. 1H NMR (400 MHz, CDCl3): δ 9.83 (s, 1H), 7.41 (m, 2H), 6.95 (d, 1H, J=8.5 Hz), 4.07 (m, 4H), 1.85 (m, 4H), 1.48 (m, 4H), 1.35 (m, 8H), 0.91 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNC
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N(C)C)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 21 from 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (23 mg, 0.062 mmol), ethanol (0.7 mL), and dimethylamine (0.461 mL, 0.923 mmol). The product was dried in vacuum oven at 50° C. for 5 hr and collected as 0.016 g (67%). LCMS E-S (M+H)=383.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.57 Hz, 6H), 2.05-2.25 (m, 6H), 3.14 (s, 6H), 4.34 (d, J=4.80 Hz, 2H), 4.99 (dt, J=13.39, 6.69 Hz, 1H), 5.89 (s, 1H), 6.94 (s, 1H), 7.96 (s, 1H), 8.64 (t, J=4.93 Hz, 1H), 11.56 (br. s., 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([OH:14])=[O:13])[CH2:3]1.[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1C[C@H](C(=O)O)Cc2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)[C@H]1CC(=O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To the stirred solution of (R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5.0 g, 26.3 mmol), K2CO3 (10.90 g, 79 mmol) and methyl iodide (6.58 ml, 105 mmol) was added in DMF (50 mL) and stirred for overnight at 25° C. Water was added (130 mL) and extracted with ethyl acetate (2×30 mL). The organic phase was washed with aq. Sodium bicarbonate solution (2×20 mL), dried over Na2SO4 and filtered. The clear organic phase was evaporated in vacuo to get title compound (4.5 g) m/z 204.09.
Reaction SMILES: [C:1]1(C([O-])=O)[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7].[K+].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1Cl.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC.O>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:18][C:19]=1[O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
73 parts by weight of potassium 3-cresolate, 107 parts by weight of 3,4-dichlorobenzotrifluoride and 6.9 parts by weight of potassium carbonate in 500 parts by volume of dimethylsulfoxide were stirred at 140° C. for 8 hours. The reaction mixture was cooled to room temperature and was poured into 2,000 parts by volume of water. The oily residue was taken up in ether, and the organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. Fractional distillation gave 120 parts by weight (84% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-toluene of boiling point 91°-96° C./0.1 bar and refractive index nD25 : 1.5268.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([CH3:31])[C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:32]([O:36][CH3:37])(=[O:35])[C:33]#[CH:34].O>CC(N(C)C)=O>[CH3:37][O:36][C:32]([C:33]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]3[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]=3[O:25][CH3:26])[CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[CH:34]=1)=[O:35]
Reactant: C#CC(=O)OC
Reactant: COc1c(NC(=O)c2cc(C)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)cc(C)c2C)nn1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
A mixture of 0.112 g (0.252 mmol) of 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4,5-dimethyl-benzamide and 0.069 mL (0.756 mmol) of methyl propiolate was stirred in 0.5 mL of DMA at 110° C. overnight. The vial was cooled to room temperature, and the contents were poured into stirring water. The precipitate was collected and chromatographed (10-60% EtOAc in hexanes). Fractions containing predominantly the major product were collected and further purified by precipitating from dichloromethane with hexanes to provide 57 mg of a white powder. The filtrate was combined with the mixed fractions from the first chromatography, and the resulting mixture was chromatographed again to provide 22 mg of the title compound as a pale yellow solid for a total yield of 79 mg (0.149 mmol; 59%), mp: 199° C. ESI MS (m/z 528, 100, M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH:20]([CH3:22])[CH3:21])[CH:5]=[O:6]
Reactant: CC(C)I
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OC(C)C
Reaction time: 0.5 h

Procedure:
A solution of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (250 mg, 1.5 mmol) in DMF (2.5 mL) was treated with potassium carbonate (812 mg, 5.9 mmol) and stirred for 30 minutes. 2-Iodopropane (500 mg, 2.9 mmol) was added over 10 minutes and reaction mixture was stirred for 20 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium chloride solution. The organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 3-fluoro-4-isopropoxy-5-methoxybenzaldehyde. To the aldehyde was added tert-butanol (6.7 mL) and 2-methylbut-2-ene (4 mL, 38.2 mmol) and the reaction mixture was cooled to 0° C. A solution of chlorite (345 mg, 3.8 mmol) and sodium dihydrogen phosphate hydrate (527 mg, 3.8 mmol) in water (6.7 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred 30 minutes. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was basified with 1 N NaOH solution and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 1 N HCl solution and extracted with EtOAc (4×50 mL). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo to afford 3-fluoro-4-isopropoxy-5-methoxy-benzoic acid (190 mg, 56%) as a white solid. ESI-MS m/z calc. 228.0. found 229.3 (M−1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[Br:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[Br:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Nc2ccccc21
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Br)c2)n1
Reaction time: 0.67 h
Yield: 46.5 %

Procedure:
Sodium hydride (60% suspension in oil, 1.2 g, 30.15 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (110 mL). Neat 3-methylpyrazole (2.47 g, 30.15 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The [2-bromo-4-fluorophenyl]-(5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step B (6 g, 18.07 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 40 minutes, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the less polar title compound (3.87 g) along with a mixture of 3- and 5-methylpyrazole regioisomers (0.860 g). The title compound (3.5 g, 51%) crystallized by sonication from hexane-ethanol, m.p. 208-209° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]2[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C.CN(C)C=O>O.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[C:13]2[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2c(Br)ccc(OCc3ccccc3)c21
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)c2c1CCC2=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 7-(benzyloxy)-4-bromo-2,3-dihydro-1H-inden-1-one (520 mg, 1.64 mmol, 1.00 equiv), ethyl prop-2-enoate (825 mg, 8.24 mmol, 5.03 equiv), PdCl2 (58 mg, 0.33 mmol, 0.200 equiv), DIEA (1.06 g, 8.20 mmol, 5.00 equiv), (o-Tol)3P (201 mg, 0.66 mmol, 0.400 equiv), N,N-dimethylformamide (15 mL). The resulting solution was stirred for overnight at 90° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic extracts were combined. The resulting mixture was washed with 1×15 mL of water and 1×15 mL of aqueous saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:4). This resulted in 500 mg (86%) of ethyl (2E)-3-[7-(benzyloxy)-1-oxo-2,3-dihydro-1H-inden-4-yl]prop-2-enoate as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)CCCC)C(N)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:31]1C=C[CH:34]=[CH:33][CH:32]=1.F[C:38](F)(F)[C:39](OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:16][CH2:17][CH2:22][CH:23]([CH2:24][CH2:25][CH2:30][C:29]2[CH:28]=[N:27][CH:26]=[CH:38][CH:39]=2)[CH2:34][CH2:33][C:32]#[N:31])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCC(CCCc1cccnc1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: c1ccncc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#CCCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 1.44 g of 8-(p-chlorophenylsulfonamido-4-[3-(3-pyridyl)-propyl]-octanamide and 0.52 mL pyridine in 5.8 mL dioxane is cooled to 0° C. and 0.51 mL trifluoroacetic anhydride is added over a period of 1 hour. The mixture is then stirred at room temperature for 3 hours. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (2×20 mL). The combined organic extracts are dried, filtered and evaporated to give 8-(p-chlorophenyl- sulfonamido)-4-[3-(3-pyridyl)propyl]octanenitrile.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:8](=[O:27])[C:7]3=[CH:28][N:29]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-:40].[Na+]>CO.C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[C@H:12]([NH:9][CH2:10][C:11]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[N:29]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[CH:28]=[C:7]([C:8]([OH:40])=[O:27])[C:6]=12)[C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OCc4ccccc4)C(C)(C)C)c(Cl)cnc32)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
Crude (R)-benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate was dissolved in MeOH/THF (50%, 5 mL). Aqueous NaOH (1N, 2 mL) was added. The reaction mixture was stirred at 50° C. for 16 h and was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (34 mg, 38.9% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 1.22-1.32 (m, 9 H) 4.92 (br. s., 1 H) 5.18 (d, J=18.95 Hz, 1 H) 5.33 (d, J=18.95 Hz, 1 H) 7.88 (s, 1 H) 8.29 (s, 1 H). [M+H] calc'd for C15H16ClN3O3, 322; found, 322.5.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]2[CH2:36]COCC2)(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15].[CH3:37][C:38]1C=CC(OS(C2C=CC=C(S(C3OCCNC3)(=O)=O)C=2)(=O)=O)=C(C=1)OCCCON.[C:69]([C:71](=[CH:75][C:76]1C=CC(O)=CC=1)[C:72]([OH:74])=[O:73])#N>>[ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]2[CH2:76][CH2:75][CH:71]([C:72]([O:74][CH2:37][CH3:38])=[O:73])[CH2:69][CH2:36]2)(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15]
Reactant: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCOCC2)c1
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(S(=O)(=O)C3CNCCO3)c2)c(OCCCON)c1
Agent: Cl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2S(=O)(=O)Oc2cc(C)cc(OCCCONC(=N)N)c2)CC1
Yield: 95 %

Procedure:
{3-[5-Methyl-3-(2-morpholinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine hydrochloride: The title compound was prepared in 95% yield from 3-[5-methyl-[3-(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.21 (t, J=8.0 Hz, 2H), 8.04 (t, J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.71 (br s, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.49 (s, 1H), 3.99 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 3.62 (t, J=4.7 Hz, 4H), 3.25 (t, J=4.7 Hz, 4H), 2.22 (s, 3H), 2.02 (t, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C21H28N4O8S2: 529.1 (M+H), 551.1 (M+Na). Found: 528.9, 550.8.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH:13](O)[CH3:14])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>C(Cl)Cl.O>[N:30]([CH:13]([C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)[CH3:14])=[N+:31]=[N-:32]
Reactant: CC(O)c1nccc(Oc2ccc(F)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(N=[N+]=[N-])c1nccc(Oc2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
Under N2 atmosphere, 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol (140 mg, 0.598 mmol) was dissolved in 3 mL anhydrous DCM. Triethylamine (0.175 mL, 1.26 mmol) was added, and the mixture was cooled to 0° C. MsCl (0.070 mL, 0.897 mmol) was added, and the mixture was stirred 15 minutes. Maintaining 0° C., DCM solvent was removed under N2 stream. Residue was taken up in 2 mL dry DMF. NaN3 (78 mg, 1.19 mmol) added, and the reaction was stirred at rt for 24 h. Mixture was poured into 20 mL water, and extracted with 20 mL EtOAc. Organic layer was washed with 20 mL brine and dried over Na2SO4. Filtered and concentrated to give 120 mg (77%) 2-(1-azidoethyl)-4-(4-fluorophenoxy)pyrimidine as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=5.7 Hz, 1H), 7.16-6.90 (m, 4H), 6.70 (d, J=5.7 Hz, 1H), 4.34 (q, J=6.9 Hz, 1H), 1.55-1.46 (m, 3H).
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1>C1COCC1.O.C(OCC)C>[Si:34]([O:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:5])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(O[Si](C)(C)C)c1ccnc(C#N)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccnc(C#N)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 4-[1-(trimethylsilyloxy)ethyl]-2-pyridinecarbonitrile (39.04 g, 0.1624 mol) in THF (200 ml) was added a solution of tetrabutylammonium fluoride in THF (1M, 178.6 ml, 0.1786 mol) at room temperature. After stirring for 0.5 h, the mixture was concentrated. The residue was diluted with ethyl acetate (300 ml) and washed with water (200 ml). The aqueous layer was then extracted with dichloromethane (200 ml×2). The combined organic layers were dried (MgSO4) and concentrated. The residual oil was dissolved in DMF (200 ml). To the solution was added tert-butyldimethylsilylchloride (36.72 g, 0.2436 mol) and imidazole (22.11 g, 0.3248 mol) at room temperture. After stirring for 19 h, diethyl ether (500 ml) and water (200 ml) were added to the mixture and the organic layer was separated. The organic layer was washed with water (100 ml×2), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:20) to give 39.23 g (92%) of the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]Br.O>CN(C)C=O.C(OCC)C>[CH3:20][O:21][C:22]([O:25][CH3:26])([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:23]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(OC)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
4-Phenylphenol (1.70 g, 10 mmol) and cesium carbonate (3.91 g (12 mmol) were stirred at room temperature under a nitrogen atmosphere in 20 mL of dimethylformamide until it appeared that no more solid was dissolving. At that point, 1.42 mL (12 mmol) of bromoacetaldehyde dimethyl acetal (2.03 g, 12 mmol) were added to the mixture via syringe and the resulting brown suspension was stirred at room temperature overnight. The mixture was then heated under reflux for two hours and then stirred at room temperature overnight. At the end of this period, 100 mL of water and 200 mL of diethyl ether were added; the organics were extracted into the ether layer, which was separated, dried over anhydrous sodium sulfate and evaporated to yield 2.10 g (81% yield) of dimethoxy-2-(4-biphenyloxy)ethane.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)=[CH:10][C:4]=2[O:3]1.CN(C)C=O.C(N(CC)CC)C.[CH3:33][O:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>O>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:36]([N:35]([O:34][CH3:33])[CH3:39])=[O:37])=[CH:15][CH:14]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2ccc(COc3ccc(N)cc3)cc2O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)Nc1ccc(OCc2ccc3c(c2)OC(C)(C)C3)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
6.9 g of 4-(2,3-dihydro-2,2-dimethyl-6-benzofuranylmethyloxy)aniline was dissolved into 70 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added thereto. 3.8 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto. After the mixture was stirred at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off and the residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 6.0 g of Compound No. 4 shown in Table 1.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:51])[NH:11][C@@H:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=2)[C@H:13]([OH:32])[CH2:14][N:15]([S:20]([C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([S:20]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][C@@H:13]([OH:32])[C@@H:12]([NH:11][C:10](=[O:51])[O:9][C@@H:3]3[C@H:4]4[C@H:5]([O:6][CH2:7][CH2:8]4)[O:1][CH2:2]3)[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][OH:43])=[CH:36][CH:35]=3)(=[O:22])=[O:21])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 101 %

Procedure:
To a stirred solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)benzyl]-2-hydroxypropylcarbamate (160 mg, 0.21 mmol) in tetrahydrofuran (3 mL) at 5° C. was added a mixture of tetrabutylammonium fluoride (0.3 mL, 1M in tetrahydrofuran) and glacial acetic acid (0.3 mL) over 2 minutes. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL) followed by saturated sodium bicarbonate (20 mL) and then brine (20 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (135 mg, quant.) as a white solid. 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.17-1.42 (2H, m), 1.92 (1H, m), 2.33 (1H, t), 2.64-2.78 (3H, m), 2.89-3.02 (2H, m), 3.24-3.29 (1H, m), 3.52-3.73 (7H, m), 3.78-3.82 (1H, m), 3.86 (2H, t), 4.78-4.82 (2H, m), 4.99 (1H, d), 5.46 (1H, d), 6.12 (2H, s), 6.73 (2H, d), 7.02-7.28 (6H, m); MS: 637 (MH+)