Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[K+].[C:3](F)([C:5]([F:31])([O:10][C:11]([F:30])([F:29])[C:12]([F:28])([O:17][C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:13]([F:16])([F:15])[F:14])[C:6]([F:9])([F:8])[F:7])=[O:4].F[C].[OH2:35]>COCCOCCOC>[C:20]([C:19]([C:18]([O:17][C:12]([C:11]([O:10][C:5]([C:3]([OH:4])=[O:35])([C:6]([F:7])([F:8])[F:9])[F:31])([F:30])[F:29])([C:13]([F:14])([F:16])[F:15])[F:28])([F:26])[F:27])([F:25])[F:24])([F:22])([F:23])[F:21]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: O
Agent: [C]F
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 2.5 h

Procedure:
A suspension of 58.1 g (1.0 mol) of flame-dried KF in 1400 ml of dry diglyme was stirred at 25° while 333 g (0.67 mol) of hexafluoropropene oxide trimer was added rapidly. The two-phase system was stirred at 25° for 2 hr, during which time about half of the fluorocarbon layer slowly dissolved. The mixture was stirred at 5°-10° while 230 g (1.0 mol) of 1 was added. The mixture was stirred at 5°-10° for 2.5 hr, then overnight at 25°, and poured into 2 l. of H2O. The aqueous layer was extracted with 100 ml of CFCl2CF2Cl, and the combined organic layers washed with 2 l. of H2O, extracted with 100 ml of conc. H2SO4, clarified with CaSO4, filtered and distilled. Hydrolysis and bubbling were apparent in the water washed. Distillation afforded major fractions of 2 and 3, bp 55°-71° (20 mm) and 140 g of crude CF3CF2CF2OCF(CF3)CF2OCF(CF3)CO2H, bp mainly 101°-104° (20 mm). Redistillation of combined fractions of 2 and 3 gave 80 g of impure 3, bp 81°-86° (80 mm) and 33.0 g (8%) of 2, bp 94°-95° (80 mm).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.O>CN(C=O)C>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][CH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:41]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.6 %

Procedure:
To a solution of Intermediate A (179 mg, 1.10 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 120 mg, 3.00 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 92b (958 mg, 1.10 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The solution was cooled, water added, and the mixture extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-16% MeOH in DCM, to give the title compound as a brown gum (216 mg, 37%). LCMS (Method 3): Rt 3.08 min, m/z 536 [MH+].
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[N:22](OCCC(C)C)=[O:23]>C1COCC1.CCOC(C)=O>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=[N:22][OH:23])[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:19])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Reactant: CC(C)CCON=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (513 mg) was added to a suspension of NaH (60% dispersion in mineral oil) (84 mg) in THF (5 ml) and the mixture was stirred at 45-50° C. for 30 minutes. After addition of isoamyl nitrite (0.27 ml), the mixture was stirred at the same temperature for 8 hours. The mixture was dissolved in EtOAc, washed with 1N HCl and brine and dried over MgSO4. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime as a solid (185 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][OH:14])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].O>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][N:8]([CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)N(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
A solution of 2-(N-tert-butoxycarbonyl-N-isopropylamino)-ethanol (3.00 g, 14.8 mmol) and benzyl bromide (2.6 ml, 22.1 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a solution of 60% sodium hydride (885 mg, 22.1 mmol) in anhydrous tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred at 60° C. for four hours. Water (100 ml) was added to the reaction mixture under ice-cooling, the temperature was returned to room temperature, and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (100 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=4/1) to give 1.30 g (30%) of the target compound.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)cccc2n1
Yield: 30 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-chlorobenzene-sulfonyl chloride (86.5 mg; 0.41 mmol) to obtain 25.5 mg. (30% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.78 (m, 4H), 7.38 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.92 (br s, 1H), 6.83 (d, J=7.6 Hz, 1H), 5.92 (br s, 2H), 3.73 (br d, J=11.6 Hz, 2H), 3.11 (br d, J=12.0 Hz, 2H), 2.84 (m, 2H), 2.62 (m, 2H). ESIMS+420.5 m/z
Reaction SMILES: [Cl:1][CH:2]([Cl:4])[CH3:3].[B:5](OC)([O:8][CH3:9])[O:6][CH3:7].C(NC(C)C)(C)C.C([Li])CCC.ClC(B(OC(C)C)OC(C)C)Cl>C1COCC1>[Cl:1][C:2]([B:5]([O:8][CH3:9])[O:6][CH3:7])([Cl:4])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(Cl)Cl
Agent: CC(C)OB(OC(C)C)C(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COB(OC)C(C)(Cl)Cl
Temperature: -78 °C

Procedure:
A modification of the procedure of Example 1 was followed. 1,1-Dichloroethane (25 ml, 0.30 mol) was used in place of dichloromethane and trimethyl borate (30 ml, 0.265 mol) was used in place of triisopropyl borate. The quantity of diisopropylamine was 40 ml and that of butyllithium was 0.25 mol. A -78° C. cooling bath was used. The yield of (I) (R3 =R7 =R8 =methyl), bp 48° C. (40 Torr), was 27 g, 55% taking into account the 14% THF indicated by NMR analysis.
Reaction SMILES: C([O:4][C@H:5]1[C:9](=[CH2:10])[O:8][C@H:7]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:6]1)(=O)C.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>N.CO>[Si:25]([O:4][C@H:5]1[C:9](=[CH2:10])[O:8][C@H:7]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:6]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C=C1O[C@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N
Agent: c1c[nH]cn1
Solvent: CO
Product: C=C1O[C@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 97.3 %

Procedure:
Compound 8 (5.2 g, 19.53 mmol) in saturated NH3 in MeOH (150 mL) was kept at room temperature for 9 h. After evaporation, the residue was dissolved in DMF (60 mL). To this were added imidazole (5.32 g, 78.12 mmol) and tert-butyldimethylsilyl chloride (8.83 g, 58.59 mmol) at 0° C. The reaction mixture was stirred at room temperature for 11 h, and then partitioned between EtOAc/H2O (250 mL/50 mL×4). Silica gel column chromatography (hexane/EtOAc=10/1) of the organic layer gave 9 (6.43 g, 97%) as a foam: UV (MeOH) λmax 266 nm (ε11600), λmin 236 nm (ε5700); 1H NMR (CDCl3) δ 0.11 and 0.14 (6H, each as s, SiMe), 0.88 (9H, s, SiBu-t), 1.92 (3H, d, J6,CH3=1.2 Hz, Me), 2.03 (1H, dt, Jgem=10.8 Hz, J1′,2′a=3.2 Hz and J2′a,3′=3.2 Hz, H-2′a), 2.61-2.68 (1H, m, H-2′b), 4.25 (1H, d, Jgem=2.2 Hz, H-5′a), 4.57 (1H, d, Jgem=2.2 Hz, H-5′b), 4.68 (1H, dd, J2′a,3′=3.2 Hz, J2′b,3′=6.8 Hz H-3′), 6.46 (1H, dd, J1′,2′a=3.2 Hz and J1′,2′b=7.2 Hz, H-1′), 7.44 (1H, d, J6,CH3=1.2 Hz, H-6), 9.12 (1H, br, NH); FAB-MS m/z 339(M++H). Anal. Calcd for C16H26N2O4Si: C, 56.78; H, 7.74; N, 8.28. Found: C, 56.61; H, 7.87; N, 8.17.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:36]=[CH:35][C:9]2[C:10]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:11]=3[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:16][C:13]=3[CH2:14][CH2:15][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl[C:44]([O:46][C:47]1[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=1)=[O:45]>C(Cl)Cl>[C:44](=[O:45])([O:46][C:47]1[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=1)[O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:12]2[C:11]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:10]=3[C:9]3[CH:35]=[CH:36][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH2:15][CH2:14][C:13]=2[CH:16]=1
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCO)ccc1C1=C2C12OCC(C)(C)CO2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc1C1=C2C12OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of alcohol 11 (0.439 g, 0.89 mmol) and pyridine (0.25 g, 3.21 mmol) in CH2Cl2 (approximately 5 mL) was added to a solution of 4-nitrophenyl chloroformate (0.30 g, 1.49 mmol) in CH2Cl2 (25 mL) at room temperature, and the reaction mixture was stirred for 20 minutes at room temperature. Solvent was evaporated under reduced pressure, and the residue was separated by chromatography (Hex:ExOAc 4:1+1.5% of Et3N) to provide 0.317 g (0.48 mmol 80%) of 12 as and 0.113 g (0.23 mmol) of starting 11. 1H NMR: 8.25 (d, J=8.8 Hz, 2 H) 7.65 (dd, J=8.4, 2.0 Hz, 2 H), 7.35, (d, J=9.2, 2 H), 6.92-6.82 (m, 4 H), 4.43 (t, J=4.4 Hz, 2 H), 4.19 (t, J=6.4 Hz, 2 H), 3.98 (t, J=4.4 Hz, 2 H), 3.92 (m, 7 H), 3.22 (d, J=10.8 Hz, 2 H), 2.43 (d, J=10.8 Hz, 2 H), 1.75 (p, J=7.2 Hz, 2 H), 1.51 (six, J=7.6 Hz, 2 H), 1.21 (s, 3H), 1.19 (s, 3 H), 0.98 (t, J=−7.2 Hz, 3 H); 13C NMR: 159.9, 159.2, 155.7, 152.7, 150.0 147.4, 145.6, 131.77, 131.63, 125.5, 124.6, 123.4, 122.0, 119.8, 119.1, 116.25, 116.19, 112.2, 112, 15, 84.1, 79.4, 70.0, 69.1, 68.4, 70.0, 67.8, 37.1, 31.5, 30.8, 22.87, 22.79, 19.5, 14.1.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.C(Cl)CCl.[CH3:10][S:11][C:12](SC)=[CH:13][N+:14]([O-:16])=[O:15]>C(Cl)CCl>[CH3:1][NH:2][CH:12]([S:11][CH3:10])[CH2:13][N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Solvent: ClCCCl
Product: CNC(C[N+](=O)[O-])SC

Procedure:
A solution of methylamine in ethanol/ethylenedichloride (112.5 ml of 33% ethanolic methylamine in 0.8 liters of ethylene dichloride; 0.94 mole) was added over 51/2 hr at 70° to a stirred solution of 1,1-bismethylthio-2-nitroethene (99.0 g, 0.6 mole) in ethylene dichloride (1.5 liters). The solution was heated to boiling and 0.7 liters of solvent were distilled off. The cooled solution was washed with 2N hydrochloric acid (0.25 liters), then with brine (0.25 liters). The solvent was removed and the residue crystallised from isopropyl acetate (0.5 liters), treating the hot solution with charcoal (10.0 g). The product (35.0 g) formed yellow prisms, m.p. 114°.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To a solution of 4-methylbenzenecarboximidamide hydrochloride (1.70 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1.5 hours. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.05 g (50.0%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4](I)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][N:17]([CH3:35])[C:18]([C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:6]1[C:5]([O:11][CH2:12][CH3:13])=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]([N:17]([CH3:35])[CH3:16])=[O:19])=[N:21][CH:22]=2)[C:3]([CH3:15])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (0.69 g, 2.0 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (0.68 g, 2.4 mmol) in 1,4-dioxane (10 mL), potassium carbonate (0.56 g, 4.1 mmol) in water (3 mL, 200 mmol) was added. The reaction was bubbled with N2. Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) was added and N2 was bubbled. Reaction was stirred overnight at 95° C. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 90% EtOAc in hexanes) to give the desired product (0.6 g, 82%). LCMS calculated for C19H22ClN2O3 (M+H)+: m/z=361.1; Found: 361.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](OC)=[O:12].[BH4-].[Li+].O>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][OH:12]
Reactant: COC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CO)cc2ccccc21
Yield: 99.9 %

Procedure:
A solution of 5.05 g of methyl 1-methylindole-2-carboxylate (prepared as described in Preparation 22) in 20 ml of anhydrous tetrahydrofuran was added dropwise to a mixture of 1.85 g of lithium borohydride and 80 ml of anhydrous tetrahydrofuran, and the resulting mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 4.30 g of the title compound, melting at 92.8°-95.2° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=1)[NH2:3]
Reactant: Clc1cc(N2CCCOCC2)ncn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CCCOCC2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 8.8 ml (9.0 g, 180.2 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 3.9 g (18.0 mmol) of 4-(6-chloropyrimidin-4-yl)-1,4-oxazepane in 25 ml of ethanol. After 16 h of stirring at 80° C., the reaction solution is concentrated under reduced pressure. The residue is triturated with cold ethanol, the precipitated solid is filtered off and the filter residue is washed with 25 ml of diethyl ether. The product is dried under reduced pressure. Yield: 1.4 g (36% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:17]=[N:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
4-methoxycarbonylphenyl boronic acid (541 mg) and 2-chloro-5-trifluoromethylpyridine (718 mg) were added to a suspension of bisbenzonitriledichloropalladium (119 mg) and 1,4-bisdiphenylphosphinobutane (131 mg) in toluene (10 ml) at ambient temperature and then ethanol (5 ml) and saturated aqueous sodium hydrogencarbonate solution (5 ml) were added to the mixture. This mixture was heated at reflux for 5 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue diisopropyl ether was added to afford the desired compound (841 mg) as a white powder which include some impurity.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=1>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:28](=[O:29])[CH:27]([O:26][C:25]1[CH:32]=[CH:33][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:35])([F:34])[F:13])=[CH:20][N:19]=2)=[CH:23][CH:24]=1)[CH3:31])[CH3:2]
Reactant: CCNCC
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
3.4 g (0.046 mol) of diethylamine and 4.8 g (0.47 mol) of triethylamine dissolved in 10 ml of benzene are dropped into the solution of 15.6 g (0.045 mol) of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl chloride in 40 ml of anhydrous benzene at 0°-5° C. under stirring. After termination of the portionwise addition, the reaction mixture is stirred for additional 2 hours whilst it is allowed to warm to room temperature. The mixture is filtered off, the precipitate is washed with a little volume of ether, the filtrate is washed first with 5% hydrochloric acid and then with saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and finally evaporated to dryness. The crude product is purified by chromatography on a column filled with silica gel of 0.063-0.2 mm particle size by using a 4:1 mixture of n-hexane/acetone for elution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20]Br.O>CN(C=O)C>[Br:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)c2c(c1)OCCO2
Temperature: 100 °C
Yield: 501.6 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxy-benzaldehyde (20.78 g, 95 mmol) in 480 ml DMF was added K2CO3 (52.95 g, 383 mmol) followed by 1,2-dibromoethane (8.7 ml, 101 mmol). The mixture was warmed to 100° C. After 18 additional 1,2 dibromoethane (1.0 mL) was added. After 2 h the mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was purified via flash chromatography (9:1 hexane/ethyl acetate) to give 8-bromo-2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde (115.82 g, 99%) as a white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[OH:28][CH2:27][C@H:23]1[N:24]([CH2:3][CH:2]([OH:1])[C:4]2[CH:13]=[CH:12][C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[CH:5]=2)[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: O=C1OCc2cc(C3CO3)ccc21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3c(c2)COC3=O)[C@H](CO)C1
Temperature: 150 °C

Procedure:
5-(Oxiran-2-yl)-2-benzofuran-1(3H)-one (1.5 g, 8.5 mmol) and commercially available (S)-4-N—BOC-2-hydroxymethyl piperazine (2.394 g, 11.07 mmol) were combined in ethanol (10 mL) in a microwave tube. The mixture was degassed then heated for 60 min at 150° C. LC-MS showed the product peak. The reaction was worked up by adding ethyl acetate and washing once with brine. The organic layer was separated, dried, and concentrated to dryness. The crude product was purified by MPLC using an 80 g Redi-sep column and eluted with 50%-100% EtOAc/hexane yielding the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCCCC1
Reactant: OCc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(OCCN2CCCCC2)cc1

Procedure:
Schemes IX through XII exemplify the synthesis of 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-1H-indol-5-ol utilizing intermediates of the present invention. Scheme IIa, described above, can be considered the first step of Scheme IX or a step prior thereto. In this step 4-hydroxybenzyl alcohol is treated with a desired aryl amino alkyl chloride to afford the corresponding alkoxy benzyl alcohol. In the specific example of Scheme IIa, 4-hydroxybenzyl alcohol is treated with 1-(2-chloroethyl)-piperidine hydrochloride in the presence of K2CO3/Me2CO to yield 4-(2-piperidinylethoxy)benzyl alcohol. Toluene and brine can be added to the resulting alcohol mixture to separate its phases. The toluene phase can then be washed Successively with aqueous alkali and brine. The resulting batch can then be concentrated and ethylene dichloride added to form a solution of the intermediate, 4-(2-piperidinylethoxy)benzyl alcohol.