Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[K+].[K+]>O=S(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:6]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (500 mg, 2.10 mmol, 1.0 eq) in SOCl2 (5 mL) was heated at 65° C. under N2 for 1 h. The solution was then evaporated in vacuo and the remaining residue dissolved in CH2Cl2 and added dropwise to a mixture of 3-methoxyaniline (220 mg. 1.9 mmol, 0.9 eq) and K2CO3 (1.4 g, 10.1 mmol, 5.0 eq) in THF (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the solution extracted with EtOAc. The combined organic extracts were washed with aqueous Na2CO3 and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a colourless oil (580 mg, 96%).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.O1CCCC1.CCCCCCC>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[B:23]([OH:24])[OH:22])=[O:16]
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester (4.225 g, 16.23 mmol) in tetrahydrofuran (40 mL) was added triisopropylborate (9.00 mL, 39.0 mmol). The solution was cooled to −78° C. and lithium diisopropylamide (12.0 mL of a 2.0 M solution in tetrahydrofuran/heptane, 24.0 mmol) was added dropwise over 5 minutes. The red solution was stirred for 30 minutes, warmed to 0° C., and quenched by the slow addition of 1N hydrochloric acid (50 mL). The mixture was allowed to warm to room temperature, stirred for 30 minutes and added to hexanes (200 mL). The layers were separated and the organic layer was washed successively with 2N hydrochloric acid (two times with 100 mL), water (100 mL), and brine (50 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was crystallized from heptane (40 mL) to provide 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (3.037 g, 62% yield) as a white solid: mp=159-160° C.; IR 3377 (br), 2963, 1703, 1371, 1308, 1171, 1131, 794, 709 cm−1; 1H NMR (400 MHz, DMSO/D2O) δ8.05 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 3.94 (s, 2H), 0.95 (s, 9H); 13C NMR (100 MHz, DMSO/D2O) δ26.69, 31.69, 74.91, 125.29, 125.75, 128.30, 129.62, 131.98 (q, J=31.8 Hz), 136.28, 142.68,166.90.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (212 mg, 2.25 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-chlorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 28; 350 mg, 1.03 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol) and 1-Hydroxybenzotriazole (166 mg, 1.23 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. Water (50 ml) was added to the mixture and the mixture was filtered to yield the title compound as a white solid. 400 mg.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])(=[O:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:38][CH2:39][N:34]([C:28]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][C:22](=[O:24])[CH3:23])[CH:27]=3)[CH2:35][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(N2CCNCC2)cc1OC(C)=O
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(OC(C)=O)c3)CC2)c(OC)nc1C

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-acetoxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. 25 yield: 62% Example 54
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][CH:23]([NH2:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:28][CH:23]([CH3:22])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(C)(=O)=O)cc(OC)c1

Procedure:
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile (0.263 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave the title compound as a syrup, 262 mg (86%). 1H NMR (200 MHz, CDCl3): δ=0.85 (s, 9H), 1.01 (d, 3H), 3.12 (s, 3H), 3.26 (m, 1H), 3.78 (s, 6H), 6.25 (d, 2H), 6.35 (t, 1H); EI SP/MS: 381 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCCl)cc1
Reactant: O=C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCc2ccc(F)cc2)CCN1
Temperature: 85 °C
Yield: 48.3 %

Procedure:
piperazinone (1.20 g, 12.1 mmol), 1-fluoro-4-(2-chloroethyl)benzene (2.45 g, 12.1 mmol) and i-Pr2NEt (3.25 g, 4.5 ml, 25 mmol) were combined in acetonitrile (25 mL) and heated to 85° C. for 2 h. The mixture was concentrated and partitioned between H2O (20 mL) and CH2Cl2 (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH2Cl2 (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH2Cl2 (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.30 g, 48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 7.00-6.94 (m, 2H), 6.45 (s, 1H), 3.39-3.35 (m, 2H), 3.20 (s, 2H), 2.78-2.62 (m, 6H).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.O=S(Cl)[Cl:16].O>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[Cl:16][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: COC(C)(C)C
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
(2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and SOCl2 (1.2 eq) is added via addition funnel. The SOCl2 is added at a rate to maintain the temperature in the reactor at 15-25° C. The temperature is increased to 30° C. for 1 hour then cooled to 20° C. then water (4 vol) is added via addition funnel maintaining the temperature at less than 30° C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na2SO4), filtered, and concentrated to afford crude 5-chloromethyl-2,2-difluoro-1,3-benzodioxole that is used directly in the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10].O>N1C=CC=CC=1>[F:6][C:7]([F:21])([F:22])[C:8]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:10])([F:12])[F:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Add 2.50 g (22 mmole) of methanesulfonyl chloride dropwise to 5.06 g (15 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-aniline in 25 ml of pyridine and allow to stand overnight. Pour the reaction into H2O and extract with Et2O. Wash the Et2O with 1N HCl and extract with 1N NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O-hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)methanesulfonanilide; m.p. 137°-139° C.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[N:15]=1)=[O:9]>C(O)=O>[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH:5]=[O:7])=[CH:20][CH:19]=2)[N:15]=1)=[O:9]
Reactant: Nc1ccc(SCc2csc(NC=O)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ccc(SCc2csc(NC=O)n2)cc1
Temperature: 50 °C
Yield: 96.1 %

Procedure:
A mixture of acetic anhydride (1.84 g) and formic acid (0.9 g) was heated at 50° C. for 0.5 hours with stirring. The solution was cooled at room temperature and to the solution was added the 2-formylamino-4-(4-aminophenylthiomethyl)thiazole (1.6 g). The mixture was stirred at room temperature for 6.5 hours and then the mixture was poured into ice-water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (1.7 g, yield: 96.7%). mp: 195°-197° C. (dec.)
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]([OH:18])[CH2:5][CH2:6][S:7]2(=[O:17])=[O:16].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[C:19]([O:18][CH:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]=2[CH3:1])[S:7](=[O:16])(=[O:17])[CH2:6][CH2:5]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2OC(=O)c1ccccc1

Procedure:
1.0 g (4.1 mmol) of 5,8-dimethyl-4-hydroxy-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid, 0.58 g (4.1 mmol) of benzoyl chloride and a spatula tip of N,N-4-dimethylaminopyridine was stirred in 10 ml of pyridine overnight. The mixture was subsequently poured onto 5 M HCl in crushed ice and extracted with ethyl acetate. The organic phase was washed with 1 M HCl (2×20 ml) and sat. NaCl solution (2×40 ml), dried over MgSO4 and concentrated using a rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:37]=[CH:38][N:39]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=4)=[O:26])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:37]=[CH:38][N:39]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)=[O:26])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCCN(c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2cc(N3CCCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
A mixture of methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamoyl)benzoate (50 mg, 0.09 mmol) and sodium hydroxide (50 mg, 1.25 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred at 40° C. for 3 h. The residue was concentrated in vacuo to ˜5 mL then adjusted pH to 2 with 1M HCl. The residue was concentrated and triturated with MeOH to give the product 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamoyl)benzoic acid (15 mg, 31%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 10.36 (s, 1H), 8.60 (d, 1H, J=7.2 Hz), 8.19 (s, 2H), 8.06-7.92 (m, 4 h), 7.45 (d, 1H, J=8.4 Hz), 6.95 (d, 1H, J=8.4 Hz), 4.18-4.07 (m, 3H), 3.99 (s, 3H), 3.91 (s, 3H), 3.07-2.99 (m, 2H), 1.98-1.88 (m, 2H), 1.70-1.64 (m, 2H). LC-MS: [M+H]+, 518, tR=1.295 min, HPLC: 95.24% at 214 nm, 95.25% at 254 nm, tR=4.981 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:18](=O)[CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.NN.[OH-].[Na+]>C(O)COCCO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CC1CCNCC1)c1cc(-c2ccccc2)nc2cc(Cl)ccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Clc1ccc2c(CCC3CCNCC3)cc(-c3ccccc3)nc2c1
Yield: 34.7 %

Procedure:
The operation is as in Example 18, starting from 13.5 g of 1-(7-chloro-2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanone prepared as indicated in Example 10, 6 g of 98% hydrazine hydrate and 2.4 g of sodium hydroxide in 200 ml of diethylene glycol. 4.5 g of 7-chloro-2-phenyl-4-[2-(4-piperidyl)-ethyl]-quinoline are obtained, the monohydrochloride of which, formed by the action of hydrochloric acid in isopropanol, melts at 195° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[C:16](F)[CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([O:19][CH3:20])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: COc1cc(F)cc(Br)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(OC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[F:30]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:30])[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Process B: (3S,4R)-1-Benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine (492 mg) was dissolved in toluene (1 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) was added and perfluoro-1-octanesulfonylfluoride (0.42 mL) was subsequently added dropwise while the mixture was chilled in an ice water bath. The reaction mixture was stirred at 2° C. for 30 min and then at room temperature for 5 hours. Subsequently, the mixture was poured on a silica gel pad and was eluted with ethyl acetate (80 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine as a milky white syrup (421 mg).
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]2[CH2:33][C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.C(O)(C)(C)C>[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([CH:20]2[CH:33]([OH:4])[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:18][CH2:19]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (354 mg, 3.15 mmol, 2.5 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester (2.6 g, 1.26 mmol, 1.0 eq) in dimethyl sulfoxide (45 mL) and tert-butanol (13 mL) under oxygen atmosphere. After 1 hour stirring under oxygen atmosphere, the reaction mixture is purged with nitrogen, and extracted with dichloromethane (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 250:1 to 100:1, v/v) to afford [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid that is further purified by preparative HPLC to obtain a white solid (70 mg, 42% yield).
Reaction SMILES: [CH3:1][C:2]1([CH2:10][CH2:11][CH3:12])[CH2:8][C:7](=[O:9])[NH:6][C:4](=[O:5])[CH2:3]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][N:6]1[C:7](=[O:9])[CH2:8][C:2]([CH3:1])([CH2:10][CH2:11][CH3:12])[CH2:3][C:4]1=[O:5]
Reactant: BrCCCCBr
Reactant: CCCC1(C)CC(=O)NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC1(C)CC(=O)N(CCCCBr)C(=O)C1
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A mixture of the IIa product prepared in Example 1 (25 g; 0.15 mole), 1,4-dibromobutane (33.5 g; 0.15 mole), and K2CO3 (40.6 g; 0.29 mole) was stirred for a period of 16 hrs in 250 mL refluxing acetonitrile. The inorganic solid was removed by filtration and the filtrate was concentrated to a oil which was distilled to give 42.5 g (95%) of a light yellow oil, b.p. 165°-190° at 0.09 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[S:33]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: O=C(NC1CCN(c2ccc(CCO)cc2)CC1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(N3CCC(NC(=O)OCc4ccccc4)CC3)cc2)cc1
Reaction time: 4 h

Procedure:
The N-(4-(2-hydroxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.38 g, 3.89 mmol) obtained in Example 7 (4) was dissolved in pyridine (7.5 ml), and p-toluenesulfonyl chloride (960 mg, 5.04 mmol) was added thereto under ice-cooling, followed by stirring for 4 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration, thereby obtaining N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.35 g, 68%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C1(C)C=CC(S(O[CH2:21][C@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:21][C@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OC[C@H]2COC(C)(C)O2)cc(C)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 4-bromo-3,5-dimethyl-phenol (500 mg, 2.49 mmol), (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (856 mg, 2.99 mmol) and K2CO3 (1.03 g, 7.45 mmol) in dimethylformamide (5 ml) was stirred at 100° C. for two hours. The reaction mixture was diluted with AcOEt, and the organic layer was then washed with water (×2), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (AcOEt-hexane) to give (S)-4-(4-bromo-3,5-dimethyl-phenoxymethyl)-2,2-dimethyl-[1,3]dioxolane as a colorless solid (749 mg, 95%).