Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is added to a suspension of 0.06 g (2.3 mmol) of NaH in 20 ml of dry THF, under an argon atmosphere. After agitation for one hour at 23° C., a solution of 0.29 g (2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is maintained for another 2 hours at 23° C. and the mixture is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, the organic phase is then washed twice with 25 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified on a silica column (eluent: 12% ethyl acetate in heptane). The pure fractions are evaporated in order to produce a colourless oil with a yield of 40%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cc(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccc(O)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10−4 mol) in dichloroethane (5 mL) is treated with 1M BBr3 in DCM (896 μL, 8.96.10−4 mol). The mixture is then heated at 80° C. for 4 hours before 1M BBr3 in DCM (896 μL, 8.96.10−4 mol) is added. The reaction mixture is then heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual BBr3. The solvent is evaporated in vacuo and this evaporation step is repeated 3 times. 1M HCl(8 mL) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water/EtOH (3/1, 24 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and with diethyl ether to give [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[C:7]2[C:6](=[O:13])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8]2)=[CH:15]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc2c(c1)C(=O)CCO2
Product: COc1ccc2c(c1)C(=O)C(=Cc1c[nH]c3ccccc13)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (10.0 g) and 3-indolecarbaldehyde were converted to present title product recrystallized from CH3OH/CH2Cl2, 16.7 g (98%), m.p. 217°-219° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C:13]1[C:14]([F:40])=[CH:15][C:16]([F:39])=[C:17]([N:19]2[C:28]3[C:23](=[C:24]([CH3:32])[C:25]([F:31])=[C:26](F)[C:27]=3[Cl:29])[C:22](=[O:33])[C:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:20]2)[CH:18]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>CN(C)C=O>[N:1]([C:26]1[C:27]([Cl:29])=[C:28]2[C:23]([C:22](=[O:33])[C:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:20][N:19]2[C:17]2[CH:18]=[C:13]([NH:12][C:10]([O:9][C:5]([CH3:7])([CH3:8])[CH3:6])=[O:11])[C:14]([F:40])=[CH:15][C:16]=2[F:39])=[C:24]([CH3:32])[C:25]=1[F:31])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)c(C)c2c1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)c(C)c2c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Sodium azide (500 mg) was added to a solution of ethyl 1-(5-tert-butoxycarbonylamino-2 4-difluorophenyl)-8-chloro-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (2 g) in N,N-dimethylformamide (20 ml), and the mixture was heated and stirred at 70° C. for 4 hours. After water and ethyl acetate were added to the reaction mixture, and an organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to column chromatography on silica gel to conduct elution with chloroform, thereby obtaining the title compound (1.75 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: CNC(=O)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: CNC(=O)COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a mixture of 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]-N-methylacetamide (120 mg, 0.35 mmol) in acetonitrile/t-butanol (4 mL/4 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. followed by the addition of an aqueous solution of sodium chlorite (630 mg, 7.00 mmol) and sodium phosphate (monobasic and monohydrate, 930 mg, 7.00 mmol) in water (5 mL) dropwise via additional funnel. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was quenched with sodium sulfite. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by pre-HPLC to give the title compound (60 mg, 47% yield) as a white solid. MS (ES+) 359.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.94-11.93 (m, 1H), 8.07 (d, 2H), 7.92 (s, 1H), 7.62 (s, 1H), 7.37 (d, 2H), 7.04 (d, 2H), 4.52 (s, 2H), 2.68 (d, 3H).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]([O:12][P:13]([CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>N1C=CC=CC=1.ClCCl>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23]([C:22]1[CH:26]=[CH:27][C:19]([CH2:18][P:13](=[O:14])([O:12][CH2:10][CH3:11])[O:15][CH2:16][CH3:17])=[CH:20][CH:21]=1)=[O:24])#[N:9]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: N#Cc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Reaction time: 12 h

Procedure:
A 15.7 g portion of anthranilonitrile was dissolved in 50 ml of pyridine. While the solution was stirred under ice-cooling, a solution of 40.7 g of 4-[(diethoxyphosphoryl)-methyl]benzoyl chloride in 50 ml of dry dichloromethane was added dropwise. The stirring was continued at room temperature for 12 hours, after which the reaction mixture was diluted with 200 ml of dichloromethane and washed with diluted hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-n-hexane to provide 25.9 g of diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzyl-phosphonate as colorless crystals.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH3:21][CH2:22]O>CCO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([O:19][CH2:21][CH3:22])=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)N1CC(CCC(=O)O)c2c(C)cc(C)cc21
Agent: Cl
Product: CCOC(=O)CCC1CN(C(C)=O)c2cc(C)cc(C)c21

Procedure:
1-Acetyl-3-(2-carboxyethyl)-4,6-dimethylindoline (3.4 g) was dissolved in EtOH (50 ml) and 10N HCl-EtOH (3.9 ml) was added, which was followed by refluxing for 30 min. EtOH was evaporated under reduced pressure and AcOEt (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 3.3 g of 1-acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindoline.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:27][C:16]1[CH:17]=[CH:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=1)=[O:28])=[O:39]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(O)c2)c1
Reaction time: 18 h
Yield: 29.6 %

Procedure:
To a mixture of 4.1c (91 mg, 0.20 mmol), 3-hydroxybenzoic acid (28 mg, 0.20 mmol), and diisopropylethylamine (104 □L, 0.60 mmol) in DMF (2 mL) was added HATU (76 mg, 0.20 mmol) and the solution stirred for 18 h. The solvent was removed and the resulting residue purified by reverse-phase HPLC eluting with a water/acetonitrile gradient containing 0.1% TFA and lyophilized to give 34 mg (30%) of the product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[O:12]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=O)C1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a suspension of LiOH monohydrate (1.06 g, 25.2 mmol) in THF (20 mL) at 0° C. to 5° C. was added 3.78 g (22.2 mmol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine, followed by a 5 mL THF rinse. To this solution was added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF. Following a 5 mL THF rinse, 0.5 mL of water was added, and the reaction mixture was allowed to warm to 20° C. with stirring. After 6 hours, the reaction was cooled to 10° C. and quenched with water (55 mL). The THF was removed under reduced pressure, MTBE (50 mL) was added, and the biphasic solution was adjusted to pH 9.0 with 4 N HCl. The layers were separated and the aqueous layer was washed with an additional 50 mL of MTBE. The aqueous layer was stirred with 130 mL of toluene and adjusted to pH 3 with 4 N HCl, and the phases were separated. The aqueous, product-containing layer was stirred with 50 mL of toluene and adjusted to pH=3.0 with 4 N HCl. The aqueous layer was separated and extracted once more with 50 mL of toluene. The combined organic extracts were concentrated in vacuo. The residue obtained was redissolved in toluene, filtered and rinsed with toluene (approx. 50 mL total). The combined filtrates were concentrated in vacuo to an oil. Toluene (25 mL) and heptane (25 mL) were aded and warmed to 50° C. The clear solution was allowed to cool until cloudy and then was seeded with N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-Valine. The resulting slurry was stirred for at least 12 hours and the product was collected by filtration and washed with heptane (5 mL). The resulting solid was dried in a vacuum oven at 50° C. to yield the desired product as a white powder.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:2]=1.[OH-].[Li+].CO>C1COCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccccc2)c1

Procedure:
The title compound was synthesized from methyl 4-(biphenyl-3-ylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.041 g, 0.124 mmol) and lithium hydroxide (0.055 g, 1.31 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 24.0 mg, 61% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.20 (m, 1H), 2.50-2.62 (m, 3H), 2.77-2.90 (m, 2H), 3.27-3.30 (m, 1H), 6.39 (s, 1H), 7.17 (d, J=7.57 Hz, 1H), 7.26-7.44 (m, 6H), 7.53-7.58 (m, 2H); LCMS-MS (ESI−) 316.2 (M−H); HPLC (UV=97.3%), (ELSD=100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[CH:9][CH:8]=1)[CH3:5].[CH3:21][O:22][C:23](=[O:36])[CH:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:25]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][C:34](=[O:35])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH:24]([C:23]([O:22][CH3:21])=[O:36])[CH3:25])=[CH:32][CH:31]=2)=[O:15])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)OCCO)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)Oc1ccc(NC(=O)OCCOC(=O)Nc2ccc(OC(C)C(=O)OC)cc2)cc1
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To 2-[4-(2-Hydroxyethoxycarbonylamino)phenoxy]propionic acid methyl ester 33 (5 g, 17.66 mmol) in toluene (50 ml) was added 2-(4-Isocyanato-phenoxy)-propionic acid methyl ester 32 (3.9 g, 17.64 mmol) at room temperature and heated to 60° C. for 30 hours. Toluene was distilled off and water (50 ml) was added. The solids were filtered and dried to give crude 34, which was purified by column chromatography on silica gel using chloroform as eluant to get pure 34 (5.5 g, 61.8%) as a white powder. M.p: 98-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.ClCC(O)C[CH:16]1[NH:21][CH2:20][CH2:19][N:18]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1.[CH3:36][C:37](C)([O-:39])[CH3:38].[K+].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]2[CH2:17][CH2:16][N:21]([CH2:36][CH:37]([OH:39])[CH2:38][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]4[C:11]=3[CH:10]=[N:9][CH:8]=[CH:7]4)[CH2:20][CH2:19]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: OC(CCl)CC1CN(C(c2ccccc2)c2ccccc2)CCN1
Reactant: Oc1cccc2ccncc12
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(COc1cccc2ccncc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 15 ml of dried THF were dissolved 80 mg of 8-hydroxyisoquinoline and 204 mg of 4-(3-(chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), and 68 mg of potassium t-butoxide was further added thereto, followed by stirring at room temperature for 20 hours. The reaction liquid was then poured into 15 ml of an aqueous saturated ammonium chloride solution, and extraction was then performed with 150 ml of methylene chloride. After drying with an anhydrous Glauber's salt, the solvent was distilled off, and the resultant residue was purified through a silica gel thin-layer chromatograph. Development was carried out by the use of an effluent solvent of chloroform:methanol=25:1 for the purpose of separation and purification, with the result that 8-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxy-propoxy]isoquinoline was obtained in an amount of 70 mg.
Reaction SMILES: C[O:2][P:3]([CH2:7][N:8]([S:10]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])=[O:11])[CH3:9])(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[S:10]([N:8]([CH2:7][P:3](=[O:2])([OH:4])[OH:6])[CH3:9])(=[O:11])=[O:12]
Reactant: COP(=O)(CN(C)S(=O)(=O)c1cccs1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)O)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (obtained as described in Example 46, step 2) (180 mg, 0.6 mmol) in dichloromethane (3 mL) at 0° C. was slowly added bromotrimethylsilane (190 μL, 1.4 mmol). The reaction was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was concentrated, the residue was redissolved in dichloromethane, and the solution was again concentrated. Methanol (10 mL) was added to the residue, and the solution was stirred at room temperature for 30 min. The solution was then filtered and concentrated. The oily residue was triturated with 1:1 ether-hexanes, and an orange solid was collected by filtration. The orange solid was boiled in dichloromethane (3 mL), cooled, and filtered to yield the title compound (120 mg, 74%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 7.87 (dd, J=1.5, 4 Hz, 1 H, Ar—H), 7.66 (dd, J=1.5, 3.5 Hz, 1 H, Ar—H), 7.25 (dd, J=4, 5 Hz, 1 H, Ar—H), 3.31 (d, J=12.5 Hz, 2 H, CH2P), 2.92 (s, 3 H, NCH3).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)=[O:48])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([OH:48])([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)[C:2]([F:4])([F:3])[F:1])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C(=O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2M solution of (trifluoromethyl)trimethylsilane in THF (0.23 ml) and a 0.1M solution of tetrabutylammonium fluoride trihydrate in THF (0.42 ml) were added to 4-{3-chloro-4-[1-methyl-2-(2-methyl-pyridin-4-yl)-2-oxo-ethyl]-phenoxy}-benzonitrile (80 mg) in THF (1 ml). The mixture was stirred for 1 h at room temperature and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:1) to give the title compound (60 mg) as a light yellow solid. MS (m/e)=447.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCCO1
Reaction time: 18 h

Procedure:
A solution of 5-bromo-o-anisaldehyde (25 g, 116 mmol), 1,3-propandiol (9 mL, 125 mmol), p-toluenesulphonic acid (0.1 g) in toluene (150 mL) was heated and water was azeotropically removed using a Dean-Stark water-separator. After 18 hours, the solution was washed with 5% Na2CO3 (100 ml), dried (K2CO3) and the solvent was removed under reduced pressure. The acetal was purified by vacuumdistillation and isolated as clear oil:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:22])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].C[Si]([N-][Si](C)(C)C)(C)C.[CH:35]1[CH:40]=[CH:39][C:38]([O:41][C:42](Cl)=[S:43])=[CH:37][CH:36]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([CH3:21])([O:22][C:42]([O:41][C:38]2[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=2)=[S:43])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(C)(O)Cc2ccccc2)COC1(C)C
Reactant: S=C(Cl)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(C)(Cc2ccccc2)OC(=S)Oc2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of (R)-4-(1-hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.50 g) in THF (25 ml) was cooled under an argon atmosphere to −78° C. and treated dropwise with 1 M lithium-bis-(trimethylsilyl)amide in THF (1.79 ml). The solution was allowed to warm to r.t. Then, phenyl chlorothionoformate (0.3 ml) was added. After stirring at r.t. for 2 hrs, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to give crude (R)-2,2-dimethyl-4-(1-methyl-1-phenoxythiocarbonyloxy-2-phenyl-ethyl)-oxazoli-dine-3-carboxylic acid tert-butyl ester as pale yellow oil which was used in the next reaction step without further purification.
Reaction SMILES: C(Cl)(=O)OCC.[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[CH:27]=1)(O)=[O:8].C(N(CC)CC)C>O1CCCC1>[OH:8][CH2:7][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[CH:27]=1
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C(=O)O)ccc2O1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)N=C(c2ccccn2)c2cc(CO)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
Ethyl chlorocarbonate(80 mg) was added to a solution of Compound 113 (200 mg) and triethylamine (0.10 ml) in anhydrous tetrahydrofuran (1 ml) at -15° C. under an argon atmosphere and the mixture was stirred at -15° to -10° C. for 30 minutes. The resulting precipitate was filtered off and the filtrate was added to a solution of sodium borohydride (67 mg) in water (0.7 ml) at 10° C. After completion of the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was extracted by addition of water and ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 6-hydroxymethyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (110 mg) (Compound 115). Likewise, Compound 145 was prepared from Compound 114.