Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])[CH:28]=1>O1CCCC1>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])[CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.075 mL) was added to [5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 99-(1); 37.3 mg, 0.0625 mmol), and the mixture was stirred for two hours. The reaction mixture was purified by silica gel chromatography (45 to 50% ethyl acetate/hexane) to give the title compound (12.7 mg, 38%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[O:5][C:4]([CH3:16])([CH3:15])[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(COC)OC.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:7]3[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=3[O:5][C:4]([CH3:16])([CH3:15])[N:3]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)N=C(Cl)c2ccc([N+](=O)[O-])cc2O1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1(C)N=C(c2ccc(F)cc2)c2ccc([N+](=O)[O-])cc2O1
Temperature: 25 °C

Procedure:
A mixture of the compound obtained in (1) described above (1.75 g), 4-fluorophenylboronic acid (1.53 g), potassium carbonate (1.55 g) and a catalytic amount of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in dimethoxyethane (30 mL) was heated under reflux under nitrogen atmosphere overnight. After cooling to room temperature, to the reaction mixture was added ethyl acetate (30 mL) and saturated brine (30 mL). The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by flush chromatography on silica gel (petroleum ether/ethyl acetate=10/0 to 10/1) to give the titled compound (1.0 g) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([O:20][CH:21]([F:23])[F:22])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+:31]>O>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]3[C:14](=[C:15]([O:20][CH:21]([F:23])[F:22])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]([C:25]([O-:27])=[O:26])=[N:11]2)=[CH:8][CH:9]=1.[Na+:31]
Reactant: O=C(O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
1-(4-Trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylic acid (120 mg) and a 1N aqueous solution of sodium hydroxide (0.265 ml) were added to water (5 ml), and the mixture was stirred at room temperature for 1 hour. The resultant mixture was washed with ethyl acetate (10 ml). After removing the water, the obtained crystals were dried to give 91 mg of desired sodium 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylate (yield: 78.4%). m.p., 165°-169° C.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.C(O[K])(C)(C)C.O.Cl>C(O)(C)(C)C>[C:13]1([C:4]2[CH:3]=[CH:2][CH2:7][CH2:6][C:5]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCC(Cl)C=C1c1ccccc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C1=C(c2ccccc2)C=CCC1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-phenylcyclohex-2-enecarboxylate (110 mg, 0.407 mmol) in tert-BuOH(2 ml), tert-BuOK(93 mg, 0.832 mmol) was added by portion on a water bath. After stirring for 1 hr. at room temperature, water was added to the reaction mixture, and it was acidified with dil. HCl aq. and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 70 mg of ethyl 2-phenylcyclohexa-1,3-dienecarboxylate (y=74.0%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.14-7.39(5H, m), 6.03-6.24(2H, m), 3.94(2H, q, J=6.9 Hz), 2.55-2.65(2H, m), 2.26-2.35(2H, m), 0.90(3H, t, J=6.9 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[N:5][NH:6]S(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[C:4](=[N+:5]=[N-:6])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1
Reactant: COC(=O)C(=NNS(=O)(=O)c1ccc(C)cc1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a dry flask under argon was placed a solution of (3,4-dichloro-phenyl)-(4-toluenesulfonylhydrazono)-acetic acid methyl ester (1.45 g, 3.61 mmol) in dichloromethane (20 mL) containing triethylamine (0.55 mL, 3.97 mmol) at 25° C. The bright yellow solution was then stirred at 25° C. for 1 h, then the solvent was removed in vacuo to yield a bright yellow solid. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 7/1/0.5 hexanes/dichloromethane/methanol) to furnish diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (814 mg, 92% yield) as a bright yellowish orange solid: EI-HRMS m/e calcd for C9H6Cl2N2O2 (M+) 243.9806, found 243.9800.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13](=[O:28])[C@@H:14]([NH:16][C:17](=[O:27])[CH2:18][NH:19][C:20]1[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=1)[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+].COC.C(O)(C(F)(F)F)=O>CCO.O.[NH4+].[Cl-]>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13](=[O:28])[C@@H:14]([NH:16][C:17](=[O:27])[CH2:18][NH:19][C:20]1[S:21][C:22]([CH2:25][OH:26])=[CH:23][N:24]=1)[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: COC
Agent: [BH4-]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)CNc1ncc(CO)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of material from Example 4 (26.7 mg, 0.050 mmol) in a mixture of EtOH/Water (4:1) (3 mL) is added sodium borohydride (18.4 mg, 0.486 mmol) in 3 portions over M5 min. The resulting pale white suspension is allowed to stir at room temp for 3 h. The reaction is diluted with EtOAC (75 mL) and saturated aqueous NH4Cl (12 mL). The water layer is back extracted with EtOAc (6×20 mL), the organic layers were combined, extracted with water (2×10 mL), brine (1×10 mL), dried over Na2SO4, filtered and evaporated to dryness. The aqueous layers were combined, evaporated to dryness, and purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 5% Solvent B to 45% Solvent B over 10 min, ret. T=4.12 min. The fractions containing the desired product were evaporated to dryness to give 7.3 mg (35%) of a 1:1 mixture of the title compound and its methyl ether as a colorless film as a TFA salt. LC/MS (Condition A): ret. T=0.8 min, (M+Na) 424.12 and ret. T=1.49 min, (M+Na) 444.12.
Reaction SMILES: [OH:1][CH2:2][C@:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.Cl.[CH3:33][NH:34][CH3:35].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:1][CH2:2][C@:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([N:34]([CH3:35])[CH3:33])=[O:27])=[CH:24][N:23]=5)=[CH:20][CH:21]=4)[CH2:14][CH2:15]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: CNC
Reactant: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)cc2)nc1
Yield: 64.6 %

Procedure:
A solution of the compound (124 mg, 0.284 mmol) obtained in Example 68-1), dimethylamine hydrochloride (116 mg, 1.42 mmol), N,N-dimethylaminopyridine (3 mg, 28 μmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.852 mmol) in N,N-dimethylformamide (2.48 mL) was stirred at room temperature for 5.5 h. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane/2-propanol (4/1), and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (ethyl acetate:methanol=2:1) to obtain the title compound (85 mg, 65%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(O)(=O)C>[C:15]1([C:13]2[N:3]3[N:4]=[CH:5][C:6]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3ccccc3)ccnc12

Procedure:
A reaction mixture comprising 4.32 g. of 3-aminopyrazole-4-carbonitrile, 7.0 g. of 3-dimethylaminoacrylophenone and 25 ml. of glacial acetic acid is refluxed for 7 hours. The mixture is evaporated and the residue is treated as described in Example 1, giving the desired product, m.p. 230°-232° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([NH:10][CH3:11])=[N:8][CH:9]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([N:10]([CH3:11])[S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ncc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in 2.0 ml of DMF, 5-chloro-2-methylamino-3-nitropyridine (0.20 g (1.07 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, p-toluenesulfonyl chloride (0.23 g (1.21 mmol)) was added. The reaction mixture was stirred under cooling with ice for 30 minutes and then at room temperature for 30 minutes, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.16 g (44%) of the title compound as pale yellow crystals.
Reaction SMILES: CC(C1C=CC(C2CCCNC2)=C(O)C=1)(C)CCCCCC.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH3:33][C:34]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:49]2)=[C:44]([O:57]CC=C)[CH:43]=1)([CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[CH3:41][C:34]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:49]2)=[C:44]([OH:57])[CH:43]=1)([CH3:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C=CCOc1cc(C(C)(C)CCCCCC)ccc1C1CCCN(CC=C)C1
Agent: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C=CCBr
Product: C=CCN1CCCC(c2ccc(C(C)(C)CCCCCC)cc2O)C1
Yield: 40 %

Procedure:
A mixture of 900 mg. (2.97 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine, 481 mg. (3.48 mmoles) of anhydrous potassium carbonate and 359 mg. (2.97 mmoles) of allyl bromide in 20 ml. of ethanol is heated at reflux for 23 hours. The reaction mixture is concentrated under reduced pressure and the residue dissolved in 250 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil is purified via column chromatography on 125 g. of silica gel eluted with 25% cyclohexane-ether to yield 172 mg. (15%) of 3-[4-(1,1-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-piperidine as an oil and 411 mg. (40%) of the title compound as an oil. Title Compound: PMR: δCDCl3TMS 0.85 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.1 (m, allyl methylene and C-2 or 6 methylene), 5.0-5.4 and 5.5-6.1 (m, three vinyl protons) and 6.8 (m, ArH).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 0.75 h

Procedure:
20 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr4-ene-3,17-dione in 100 ml of pyridine can be reacted over a period of 2 hours with 50 ml of acetic anhydride at 25° C. Then, 5 ml of water is added at 0° C., and it is stirred for 45 minutes. It is extracted with diethyl ether, washed with 2N sulfnuiric acid, pyridine-free, and the solution is neutralized in succession with saturated sodium bicarbonate solution and water. After drying and concentration by evaporation in a vacuum, the crude product is chromatographed on silica gel with a hexane-ethyl acetate-gradient. 17 g of 7α-(5-acetoxypentyl)-11β-fluoro-estr-4-ene-3,17-dione with a melting point of 78.4° C. is obtained.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]\[C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1)=[O:6])([CH3:4])[CH3:3].[CH3:19][Li]>C1(C)C=CC=CC=1>[CH3:4][C:2]([S:5]([NH:7][C@@H:8]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=1)[CH3:19])=[O:6])([CH3:1])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)(C)S(=O)/N=C\c1cnc(C(F)(F)F)nc1
Solvent: Cc1ccccc1
Product: C[C@@H](NS(=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
To a solution of 2-methyl-N-{(1Z)-[2-(trifluoromethyl)pyrimidin-5-yl]methylene}propane-2-sulfinamide (14.3 g, 51.2 mmol) in toluene (260 mL) at −70° C. was added methyllithium (1.6 M; 35.0 mL, 56.0 mmol). The mixture was stirred at −70° C. for 15 min. The mixture was quenched with saturated aqueous ammonium chloride and the reaction was allowed to warm to ambient temperature. The mixture was extracted with dichloromethane (3×). The combined organic extracts was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→35% hexanes/ethyl acetate then 100% ethyl acetate—94% ethyl acetate/methanol) gave the title compound (7.23 g). MS 240.0 [(M+1)−56].
Reaction SMILES: Cl.[CH3:2][C:3]([O:6][C:7](=[O:22])[CH2:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([CH3:5])[CH3:4].CN1CCOCC1.[C:30]([S:38][CH2:39][CH2:40][C:41](Cl)=[O:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:5][C:3]([O:6][C:7](=[O:22])[CH2:8][N:9]([C:41](=[O:42])[CH2:40][CH2:39][S:38][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)([CH3:2])[CH3:4]
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN[C@H]1CC[C@H](c2ccccc2)CC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)CCSC(=O)c1ccccc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a mixture of the compound of Example I (0.60 g, 0.0018 mole) and CH2Cl2 (6 ml) was added N-methylmorpholine (0.44 g, 0.0043 mole). The resulting mixture was cooled on an ice bath and 3-benzoylthiopropanoyl chloride (0.45 g, 0.0020 mole) was added dropwise. After stirring 10 min the mixture was filtered removing the insolubles. The CH2Cl2 solution was washed with 20% citric acid, H2O, 10% NaHCO3, H2O and dried over MgSO4. The filtered solution was concentrated under reduced pressure to dryness and then azeotroped with diethyl ether to a semi-solid residue. This residue was dissolved in a small amount of diethyl ether and precipitated with hexane to give a crystalline solid. Drying in vacuo at 60° overnight gave 0.48 g (0.001 mole, 55%) of trans-N-(3-benzoylthio-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine-1,1-dimethylethyl ester.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH:26]([OH:29])[CH2:27][OH:28]>C(#N)C>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: O=c1c2ccccc2sc2c(O)ccc(F)c12
Agent: [K+]
Solvent: CC#N
Product: O=c1c2ccccc2sc2c(OCC(O)CO)ccc(F)c12

Procedure:
The reactant 1-fluoro-4-hydroxy-thioxanthen-9-one was prepared as described above in Example 1a. To a suspension of 1-fluoro-4-hydroxy-9H-thioxanthen-9-on (92%) (306 g, 1.14 mol) in acetonitrile (3500 mL), potassium carbonate (464 g, 3.36 mol) was added while stirring vigorously. 3-Chloro-1,2-propanediol (371 g, 3.36 mol) was added drop wise over 30 minutes. The reaction mixture was heated to reflux and allowed to stir for 24 hours. The mixture was filtered and the residue washed with warm acetonitrile (500 mL) (70° C.). The filtrate was evaporated under reduced pressure. The residual solid was treated with a mixture of methyl-tert-butylether (400 mL) and acetone (40 ml) and stirred for about an hour. The crude 4-(2,3-dihydroxy-propoxy)-1-fluoro-thioxanthen-9-one was isolated by filtration and dried. The crude 4-(2,3-dihydroxy-propoxy)-1-fluoro-thioxanthen-9-one was treated twice with 1000 mL water at 60° C., isolated by filtration and dried.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:21][NH2:22]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([NH:22][CH3:21])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)C=Cc1ccc(OCc2ccc(F)cc2)cc1
Product: CNC(=O)C=Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 21 %

Procedure:
The title compound is prepared in analogy to example 12 b) from 3-[4-(4-fluoro-benzyloxy)-phenyl]-acrylic acid and methylamine. Yield=21%. Colorless solid. MS: m/e=286.0 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:6][NH:7][C:8](=O)[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]([CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=2)=[N:7][CH2:6]1)=[O:30])[CH3:2]
Reactant: CCOC(=O)C(CNC(=O)Cc1cc(C)cc(OC)c1)c1ccc(OC)c(OC)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CN=C(Cc2cc(C)cc(OC)c2)c2cc(OC)c(OC)cc21
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A solution of 2-(3,4-dimethoxy-phenyl)-3-[2-(3-methoxy-5-methyl-phenyl)-acetylamino]-propionic acid ethyl ester (0.79 g, 1.9 mmol) and phosphorus pentachloride (0.59 g, 2.85 mmol) in dry methylene chloride (25 mL) was stirred at room temperature overnight. A cold, saturated aqueous sodium bicarbonate solution (75 mL) was added to the reaction mixture and stirred for 1 hr. The layers were separated and the aqueous layer extracted with methylene chloride (2×25 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 6,7-dimethoxy-1-(3-methoxy-5-methyl-benzyl)-3,4-dihydro-isoquinoline-4-carboxylic acid ethyl ester as a light green oil (0.73 g, 97%). This material was used without further purification: 1H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([C:50](O)=[O:51])[NH:32][C:33]([O:35][CH2:36][CH:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:18]([O:22][C:23](=[O:53])[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([NH:32][C:33]([O:35][CH2:36][CH:37]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:44]3[C:49]2=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:34])[C:50](=[O:51])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[C:9]2[NH:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 182 mg (0.8 mmol) of 2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 390 mg (0.8 mmol) of 4-[2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid tert-butyl ester, 216 mg (1.6 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 192 mg of 1-hydroxybenzotriazole hydrate was added 2.5 mL of dimethylformamide. The mixture was allowed to stir at room temperature overnight. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated to 670 mg of crude product.