Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[OH:22]S(O)(=O)=O>>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:13])[CH:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]2=[O:22]
Reactant: COc1ccc(C2=C(N)c3cc(OC)ccc3C2=O)cc1
Reactant: O=S(=O)(O)O
Product: COc1ccc(C2C(=O)c3ccc(OC)cc3C2=O)cc1
Yield: 99 %

Procedure:
3-Amino-5-methoxy-2-(4-methoxyphenyl)-1H-inden-1-one (500 mg, 1.78 mmol), was suspended in a solution of 20% H2SO4 and heated to 120° for 1 h. The reaction was allowed to cool and the residual solid filtered and the filter cake was washed copiously with water and dried in vacuo to give a light white solid (0.5 g, 99% yield, m.p. 163° C.);
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=O)[C:4]([CH3:14])([CH3:13])[O:3]2.[NH2:15][NH2:16]>C(O)C>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=[N:15][NH2:16])[C:4]([CH3:14])([CH3:13])[O:3]2
Reactant: NN
Reactant: CC12CCC(C(=NO)C1=O)C(C)(C)O2
Solvent: CCO
Product: CC12CCC(C(=NO)C1=NN)C(C)(C)O2

Procedure:
A mixture of 1.97 g. (0.01 mole) 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime and 0.35 ml. (0.011 mole) anhydrous hydrazine (98%) in 25 ml. absolute ethanol is refluxed under nitrogen at a bath temperature of 80° C. for 1 hour. After evaporation of the solvent, the residue is recrystallized from ether to give 1,3,3-trimethyl-2-oxabicyclo [2,2,2]octan-5,6-dione-5-oxime-6-hydrazone; mp. 138° to 142° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[OH:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([NH:1][C:11](=[O:13])[CH3:12])=[C:7]([CH3:8])[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)c(C)cc1N
Solvent: O
Product: CC(=O)Nc1cc(C)c(O)cc1C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
To a suspension of 4-amino-2,5-dimethyl-phenol (6.85 g, 50 mmol) in 30 mL of water was added acetic anhydride (5.67 mL, 60 mmol). The mixture was vigorously stirred at 70° C. for 20 min and then cooled down to room temperature. The solid was collected by filtration and washed with water to give N-(4-hydroxy-2,5-dimethyl-phenyl)-acetamide as gray solid (8.1 g, 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([OH:11])=[C:5]1[CH3:12].[CH2:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]2[CH:9]=[CH:8][C:7](=[O:10])[C:6]([OH:11])=[C:5]2[CH3:12])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: C#CCN1CCNCC1
Reactant: Cc1c(O)c(=O)ccn1CCCl
Product: C#CCN1CCN(CCn2ccc(=O)c(O)c2C)CC1

Procedure:
The title compound was prepared as described in Scheme D by reaction of N-(2-chloroethyl)-2-methyl-3-hydroxy-4-pyridinone (H2, Appendix VII) (prepared as described in Bijaya L. Rai, Lotfollah Dekhordi, Hicham Khodr, Yi Jin, Zudong Liu, and Robert C. Hider J. Med. Chem. 1998, 41, 3347-3359) with N-propargylpiperazine (obtained as in step (iii) in Example 2):
Reaction SMILES: [C:1]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:46][CH3:47])[CH2:11][N:10]([C:12](=[O:41])[C@@H:13]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C@H:9]([C:42]([O:44]C)=[O:43])[CH2:8]2)=[CH:3][CH:2]=1.CO.O>O1CCCC1>[C:1]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:46][CH3:47])[CH2:11][N:10]([C:12](=[O:41])[C@@H:13]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])[C@H:9]([C:42]([OH:44])=[O:43])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
A mixture of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-4-methoxypyrrolidine-2-carboxylate (185 mg, 0.246 mmol) and LiOH monohydrate (118 mg, 4.93 mmol) in tetrahydrofuran (2 mL)/MeOH (0.5 mL)/Water (1 mL) was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo and diluted with 5 mL of water. It was then washed with ether. The aqueous phase was adjusted to pH=4 using 1N HCl. It was then extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo to yield 160 mg (87%) of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-4-methoxypyrrolidine-2-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:9][CH:10]=1)=[O:49]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)c4cccc(F)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.375 g of benzyl 4-[4-(2-aminoethoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.094 g of 3-fluorobenzoic acid in 6 ml of dichloromethane and 1.5 ml of N,N-dimethylformamide is admixed with 0.127 g of 3-dimethylaminopropyl ethyl carbodiimide hydrochloride and 0.167 g of 4-dimethylaminopyridine and stirred at room temperature over 18 hours. The reaction mixture is concentrated by evaporation and the residue partitioned between ethyl acetate and water. The organic phase is washed with 1N HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.39 (95:5 dichloromethane-methanol); Rt=5.25.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:4][C:3]1[C:3]2[C:4](=[O:14])[CH2:5][CH:6]([C:8]3[S:9][CH:10]=[CH:11][C:12]=3[CH3:13])[CH2:7][C:2]=2[N:1]=[CH:7][CH:2]=1
Reactant: Cc1ccsc1C1CC(=O)C=C(N)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccsc1C1CC(=O)c2c(C)ccnc2C1
Yield: 137.2 %

Procedure:
To a solution of 1-amino-5-(3-methyl-2-thienyl)cyclohexen-3-one (2.7 g) in ethanol (50 ml) and toluene (150 ml) were added acetylacetoaldehydedimethylacetal (4.3 g) and 85% potassium hydroxide (0.71 g), and the mixture was refluxed. With 30 minutes interval, 85% potassium hydroxide (0.15 g) was added thrice to the mixture, and the mixture was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give crystals of 4-methyl-7-(3-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].Cl>C(Cl)(=O)C>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[C:15](=[O:17])[CH3:16]
Reactant: CCc1c(F)cccc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1c(F)ccc(C(C)=O)c1Cl
Temperature: 40 °C
Yield: 38.5 %

Procedure:
A mixture of 1-chloro-2-ethyl-3-fluorobenzene (8.0 g) and anhydrous aluminum chloride (13.09 g) was stirred at 40° C., acetyl chloride (3 drops) was added thereto, and the mixture was stirred for 10 min. The mixture was cooled to room temperature, acetyl chloride (3.9 g) was added to the mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and 2 mol/L hydrochloric acid was added thereto. The mixture was extracted with methylene chloride (240 mL), washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) to give the title compound as a colorless oil (yield: 3.84 g).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3>O>[CH3:3][CH2:2][CH:1]=[CH:5][CH2:4][CH2:8][CH2:7][CH2:6][CH2:10][CH3:9]
Reactant: C1=CC2C3C=CC(C3)C2C1
Solvent: O
Product: CCC=CCCCCCC

Procedure:
The invention therefore consists in a process for preparing 3(4),8(9)dihydroxymethyltricyclo[5.2.1.02,6]decane by hydroformylating dicyclopentadiene with subsequent hydrogenation. The process comprises reacting dicyclopentadiene, in a first hydroformylation stage in a heterogeneous reaction system using an aqueous solution of transition metal compounds, containing water-soluble organic phosphorus (III) compounds in complex-bound form, of group VIII of the Periodic Table of the Elements at temperatures of from 70 to 150° C. and pressures of from 0.5 to 10 MPa, with synthesis gas to give 8(9)-formyltricyclo[5.2.1.026]dec-3-ene, then separating the organic phase from the aqueous phase and subsequently converting the thus obtained 8(9)formyltricyclo[5.2.1.02,6]dec-3-ene, in a second hydroformylation stage in homogeneous organic phase in the presence of transition metal compounds of group VIII of the Periodic Table of the Elements at temperatures of from 70 to 140° C. and pressures of from 5 to 35 MPa by reacting with synthesis gas, to 3(4),8(9)-bisformyltricyclo[5.2.1.02,6]decane and subsequently hydrogenating the thus obtained 3(4),8(9)-bisformyltricyclo[5.2.1.02,6]decane to give 3(4),8(9)-dihydroxymethyltricyclo[5.2.1.02,6]decane.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6])[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: N#Cc1ccnc(Cl)c1
Product: CCCN(CCC)c1cc(C#N)ccn1
Temperature: 100 °C

Procedure:
2-Chloroisonicotinonitrile (1.0 g) and dipropylamine (10 mL) were placed in a sealed heavy wall tube and heated to 100° C. for 18 h. The mixture was removed from heat and cooled to room temperature. The dipropylamine was removed under reduced pressure and the residue chromatographed on silica gel using 2% ethyl acetate in hexanes as eluent to give 1.06 g of the title compound: MS (ESI+) for C12H17N3 m/z 204.1 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][CH:20]=1
Reactant: OC1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(Cc2ccc(F)cc2)CCNCC1
Reaction time: 14 h
Yield: 98.4 %

Procedure:
A mixture of 1-benzyl-4-(4-fluorobenzyl)-4-hydroxypiperidine (520 mg, 1.7 mmol), 5% Pd/C (150 mg) and EtOH (15 mL) was shaken under H2 (30 psi) for 14 h and filtered. The filtrate was evaporated to give 350 mg (98%) of the title compound as a yellowish oil. 1H NMR (CDCl3), 1.45-1.64 (m, 6H), 2.792 (s, 2H), 2.63-2.96 (m, 4H), 6.97-7.02 (m, 2H), 7.14-7.19 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[CH3:11][C:12]([C:14](Cl)=[O:15])=[CH2:13].O>O1CCCC1>[C:14]([O:4][CH2:3][CH2:2][Cl:1])(=[O:15])[C:12]([CH3:13])=[CH2:11]
Reactant: OCCCl
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloroethanol of 6.7 ml (0.1 mol) and 8.9 ml (0.2 mol) of pyridine were added to 200 ml of tetrahydrofuran. A solution in which 10.7 ml (0.11 mol) of methacryl chloride was dissolved in 50 ml of tetrahydrofuran was added dropwise in 30 minutes to the resulting solution, stirred at room temperature for one hour, and mixed with water. The resulting mixture was extracted with ethyl acetate. The extraction solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-chloroethyl methacrylate. DABCO of 11.2 g (0.1 mol) and 11.5 g (0.1 mol) of benzyl chloride were added to 100 ml of ethanol and heated under reflux for 48 hours. The reaction mixture was filtered off to obtain a solid, and the solid was washed with acetone to obtain N-ethyl-DABCO monoammonium chloride (Compound D). Compound D of 11.9 g (0.05 mol), 7.4 g (0.05 mol) of 2-chloroethyl methacrylate, and 0.9 g (0.005 mol) of t-butylcatechol were added to 50 ml of ethanol and heated under reflux for 48 hours. The reaction mixture was filtered off to obtain a solid, and the solid was washed with acetone to obtain 10.5 g of ASM-4. The chemical structure of ASM-4 was confirmed according to 1H-NMR and IR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2Cl>>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2[NH:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: Clc1cnc2c(Cl)nccc2c1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(Nc3nccc4cc(Cl)cnc34)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The titled compound was synthesized by procedure and steps analogous to those described in Method B, Step 2, Example 8 above, but using (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (17i, Example 163, Method Y step 9) in step 2 and 3,8-dichloro-1,7-naphthyridine (intermediate 2). MS m/z=472.1 [M+H]+. Calculated for C20H15ClF5N50: 471.8
Reaction SMILES: [N:1]1([CH2:6][CH:7]=[N:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[CH:18]([N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])=[CH2:19].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH2:19][CH:18]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[O:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=CCN1CCCC1
Reactant: C=CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CCCN1C1CC(CN2CCCC2)=NO1
Yield: 11 %

Procedure:
To a solution of 504.1 mg (3.93 mmol) of pyrrolidin-1-yl-acetaldehyde oxime prepared in Example 3 in 5 mL of tetrahydrofuran, 578 mg (1.1 equivalent) of N-chlorosuccinimide (NCS) was added, and then the mixture was reacted at 50° C. for 1 hour. To this solution, a solution of 630 μL (1.5 equivalent) of N-vinyl pyrrolidin-2-one in 30 mL of toluene was added, and 630 μL (1.1 equivalent) of triethylamine was added. After completion of the reaction, chloroform and a saturated aqueous solution of sodium carbonate were added, the mixture was extracted with chloroform three times, washed with a saturated aqueous solution of sodium carbonate twice following water once, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The dried compound was purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 30:1 to 20:1) as eluent to obtain 102.2 mg (11% yield) of 1-[3-(pyrrolidin-1-yl-methyl)-4,5-dihydro-isoxazol-5-yl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([C@@H:24]([N:29](C)[C:30](=O)OC(C)(C)C)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:38].O1CCOCC1>O1CCOCC1>[ClH:38].[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22]([C@@H:24]([NH:29][CH3:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C[C@@H](C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](CC(C)C)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
344 mg (0.69 mmol) of t-butyl (1S)-1-{[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]carbonyl}-3-methylbutyl(methyl)carbamate was dissolved in 2 ml of 1,4-dioxane. 4 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred at room temperature for 5 hours and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:43])([C:14](=O)[NH:15][CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:44])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:43])([C:14]2[S:54][C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=3)=[CH:16][N:15]=2)[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCCc2ccccc2)c(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1ncc(-c2ccc(OCCCCCCc3ccccc3)c(C(F)(F)F)c2)s1
Temperature: 80 °C

Procedure:
To a solution of (R)-tert-butyl 2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate (49 mg, 0.079 mmol, 1.0 equiv) in toluene (1 mL) was added Lawesson's reagent (32 mg, 0.087 mmol, 1.1 equiv). The reaction mixture was heated at 80° C. for 3 h. The crude product was purified directly by SiO2 column chromatograph (EtOAc/hexanes, 3:7) to give (R)-tert-butyl 2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate. HPLC retention time on a C8(2) column (30×50 mm, 3μ) is 3.29 min with gradient 70-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=619.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:8][C:7]1[C:6]([F:10])=[CH:5][C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of N′-(3-chloro-5-fluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethylformimidamide (600 mg, 2 mmol) in DCM (10 mL) at 0° C. were added PPh3 (1.06 g, 4.06 mmol) and CBr4 (1.3 g, 4.06 mmol). The resulting solution was stirred at room temperature for 30 min, concentrated, and purified by column chromatography (silica, DCM/EtOAc=20:1) to afford N′-(4-(bromomethyl)-3-chloro-5-fluorophenylsulfonyl)-N,N-dimethylformimidamide (673 mg, 92%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.18-8.11 (m, 1H), 7.78 (d, 1H), 7.57 (dd, 1H), 4.64 (d, 2H), 3.22 (d, 3H), 3.10 (t, 3H); MS (EI) m/z 379 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C=CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C=CCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Acylation of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propenyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride analogously to the procedure described in Example 22(k) yielded tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propenyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 578 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 83.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (500 mg, 0.9 mmol), 4-methylsulfonyl phenylboronic acid (540 mg, 2.7 mmol) and dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 40% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (405 mg, 83%) as a light yellow solid: LC/MS m/e calcd for C27H25FN2O5S2 [M+H]+ 541.64, observed 541.2.