Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:17][O:18][C:19](=[O:37])[C@H:20]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)[NH:21]C(OC(C)(C)C)=O.[Cl-].[NH4+]>C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:37])[C@H:20]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:21]
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of zinc dust (30 mmol, 2.0 g) in THF (3.0 mL) was added 1,2-dibromoethane (2.0 mmol, 0.174 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased (observed). This process was repeated three times. Then, the suspension was cooled to r.t. and trimethylchlorosilane (1.0 mmol, 0.15 mL) was added and the mixture was stirred for 10 min. A hot (the iodo compound was not very soluble in either solvent and it precipitated upon cooling to room temperature) solution of 5-iodo-1,3-dimethyluracil (11.0 mmol, 2.92 g) in THF (3.0 mL) and DMA (10 mL) was added to the zinc suspension. After addition, the mixture was heated to 73° C. The internal temperature of the reaction mixture rose to 77-78° C., due to the exothermic reaction. The reaction mixture was stirred at a bath temperature of 73° C. for 1.5 h and then was cooled to room temperature and stirred another 1.5 h. 1H-NMR of a hydrolysate of a 0.25 mL aliquot of the mixture indicated the presence of traces of starting material and iodolysis of a 0.25 mL aliquot of the mixture gave the iodide back. The reaction mixture was heated to 70° C. and stirred for another 30 min. The reaction mixture was diluted with THF (5 mL) after cooling to room temperature and the excess zinc was allowed to settle for 30-60 min. The above prepared zinc compound (5.5 mmol) was added to a suspension of Pd(dba)2 (0.07 mmol, 40 mg), trifurylphosphine (TFP) (0.26 mmol, 66.6 mg) and Boc-4-iodo-L-phenylalanine methyl ester (4.5 mmol, 1.823 g) in THF (10 mL) at room temperature and the light yellow mixture was stirred for 15 h. The mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solution gave the crude product which was purified by column chromatography to obtain 0.80 g (43%) of N-[(1,1-dimethylethoxy)carbonyl]-4-[1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)]-L-phenylalanine methyl ester as a white solid: mp 65-69° C. EI-HRMS m/e calcd for C21H27N3O6 (M+) 418.1978, found 418.1965.
Reaction SMILES: [OH-].[K+].Cl.[CH3:4][NH:5][CH3:6].[C:7]1([CH3:34])[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:22][C:21](=O)[CH2:20][N:19]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[C:7]1([CH3:34])[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:22][CH:21]([N:5]([CH3:6])[CH3:4])[CH2:20][N:19]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(=O)C2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(N(C)C)C2)cc1
Reaction time: 25 h
Yield: 50 %

Procedure:
Addition of 102 mg (1.8 mmol) of potassium hydroxide to a solution of 479 mg (5.9 mmol) of dimethylamine hydrochloride in methanol (4 ml) gave a clear solution. To this solution were added 979 mg (2.3 mmol) of 1,4-bis(p-toluenesulfonyl)-6-oxohexahydro-1,4-diazepine synthesized by the above process in methanol (30 ml) and 116 mg (1.8 mmol) of sodium cyanoborohydride. After the resultant mixture was stirred for 15 hours at room temperature, 104 mg (1.7 mmol) of additional sodium cyanoborohydride was added, and the mixture was stirred for an additional 25 hours. A 1N aqueous solution (5 ml) of sodium hydroxide was added to the reaction mixture, and the mixture was concentrated under reduced pressure, followed by extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 519 mg (yield: 50%) of 1,4-bis(p-toluenesulfonyl)-6-(N,N-dimethylamino)-hexahydro-1,4-diazepine as a colorless oil.
Reaction SMILES: [CH2:1]1[CH2:37][O:36][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:44][S:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Cl-].[Li+]>[CH2:37]1[CH2:1][O:2][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:22]=[CH:23][C:24]([C:49]5[CH:50]=[CH:51][C:46]([S:45][CH3:44])=[CH:47][CH:48]=5)=[CH:25][CH:26]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:36]1
Reactant: C[C@]12C[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)[C@H]3[C@@H](CC=C4CC5(CC[C@@H]43)OCCO5)[C@@H]1CCC2=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CC=C5CC6(CC[C@@H]5[C@H]43)OCCO6)cc2)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 100.2 %

Procedure:
1.73 g of 3,3-(ethylenedioxy)-11β-(4-trifluoromethylsulfonyloxyphenyl)-5-estren-17-one is dissolved in a mixture of 17 ml of toluene and 5 ml of ethanol and mixed in succession with 37 mg of palladiumtetrakistriphenylphosphine, 0.28 mg of lithium chloride, 4 ml of 2 m sodium carbonate solution and 0.7 g of [4-(methylthio)phenyl]boronic acid. The reaction mixture is then stirred for 6 hours at 95° C., cooled to room temperature and mixed with saturated sodium chloride solution. The organic phase is separated, washed in succession with 5% sodium hydroxide solution and water, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 1.65 g of the title compound is obtained as white foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[C:4]([CH3:16])=[N:3]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.O1CCCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][CH:15]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(C)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 58 %

Procedure:
3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)benzaldehyde (2.05 g, 9.57 mmol) was dissolved in a mixed solution of 1,2-dimethoxyethane (10 mL) and tetrahydrofuran (10 mL), sodium borohydride (0.265 g, 7.00 mmol) was added under ice-cooling, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 3 hr. Dilute aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) to give the title compound (1.20 g, yield 58%) as a colorless oil. MS: m/z 217 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Methyl 2-fluoro-4-nitrobenzoate (1.05 g, 5.273 mmol) was dissolved in MeOH. Pd/C (105 mg) was added to the resulting mixture. The reaction mixture was stirred at room temperature for 2 hours under H2. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound methyl 4-amino-2-fluorobenzoate (870 mg, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Li+].CC([N-][CH:13]([CH3:15])[CH3:14])C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1(Br)CC1.[NH4+].[Cl-]>C1COCC1>[CH:13]1([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccncc1
Reactant: CC(C)[N-]C(C)C
Agent: BrC1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: c1cc(CC2CC2)ccn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a −78° C. solution of 4-picoline (1.1 g, 11.8 mmol) in THF (5 mL) was added a solution of LDA 2M in THF/heptane/ethylbenzene (Aldrich) (5.9 mL, 11.8 mmol) the resulting reaction mixture was stirred at −78° C. for 3 h then −40° C. for 1 h. Then cyclopropyl bromide (1.43 g, 11.8 mmol) was added at −78° C., let it warm up to room temperature and stirred at room temperature for 1 h. To the reaction mixture was added saturated aqueous NH4Cl (10 mL) the aqueous phase was extracted with EtOAc (10×2 mL) and the combined organic extracts dried over Na2SO4. The solvent was removed and the product 4-cyclopropylmethylpyridine (0.5 g, 31%) was obtained and used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([NH2:7])[CH3:6].Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH:16]=2)[CH:12]=[CH:11][N:10]=1>>[F:28][C:24]1[CH:23]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH:5]([CH3:6])[CH2:4][CH2:3][O:2][CH3:1])[N:14]=3)[CH:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COCCC(C)N
Reactant: Fc1cccc(Nc2cc(-c3ccnc(Cl)n3)ccn2)c1
Product: COCCC(C)Nc1nccc(-c2ccnc(Nc3cccc(F)c3)c2)n1

Procedure:
The title compound was prepared from 3-methoxy-1-methylpropylamine (i.e., the product of Step B) and 4-(2-chloro-4-pyrimidinyl)-N-(3-fluorophenyl)-2-pyridinamine (i.e., the product of Example 17, Step C) in the same fashion as described in Example 17, Step D to give the title compound as a yellow solid, m.p. 104-106° C.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C@@H:24]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](=[O:79])(=[O:78])[NH:41][C:42](=[O:77])[C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][CH:52]([C@@H:55]([O:69][Si](C(C)(C)C)(C)C)[C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:51][CH2:50]4)=[CH:45][CH:44]=3)=[CH:36][C:35]=2[S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:17]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C@@H:24]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](=[O:79])(=[O:78])[NH:41][C:42](=[O:77])[C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][CH:52]([C@H:55]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:62]5[CH:63]=[CH:64][C:65]([Cl:68])=[CH:66][CH:67]=5)[OH:69])[CH2:51][CH2:50]4)=[CH:47][CH:48]=3)=[CH:36][C:35]=2[S:80]([C:83]([F:84])([F:86])[F:85])(=[O:81])=[O:82])[CH2:25][S:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:20][CH2:21]1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(N[C@H](CCN2CCN(CCOP(=O)(O)O)CC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Yield: 34.7 %

Procedure:
Di-tert-butyl 2-(4-((R)-3-(4-(N-(4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperazin-1-yl)ethyl phosphate (INTERMEDIATE 62,414 mg, 0.32 mmol) was dissolved in DCM (0.5 ml) and treated with a solution of HCl (4M in dioxane, 4.0 ml, 15.84 mmol) at rt, to provide a cloudy solution. The reaction mixture was concentrated under reduced pressure to provide an oily residue which was purified by reverse phase HPLC (Gilson column, eluting with 20→95% MeCN in 10 mM NH4OAc with 5% MeCN over 15 min). The collected fractions were concentrated and washed with water and filtered to remove NH4OAc and provide the title compound (120 mg, yield: 35%).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH2:17][CH2:16][O:15][CH2:14][O:13][CH3:12])[C:3]=1[CH:4]=[O:5]
Reactant: COCOCCBr
Reactant: O=Cc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCCOc1ccc(F)c(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3-difluoro-6-hydroxybenzaldehyde (2.17 g), 2-(methoxymethyloxy)-ethyl bromide (1.92 mL), potassium carbonate (2.85 g) and sodium iodide (0.41 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-1/1) to give 2,3-difluoro-6-[2-(methoxymethyloxy)ethoxy]benzaldehyde (1.02 g). This material was dissolved in tetrahydrofuran (15 mL). To the solution were added water (1.5 mL) and sodium borohydride (92 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 10% aqueous sodium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([S:10]C(=O)N(C)C)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:16]([C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[SH:10])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(SC(=O)N(C)C)c(C(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CO)ccc1S
Temperature: 25 °C

Procedure:
A solution of 2.1 g (7.1 mmol) of 3-tert-butyl-4-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (Example W) in toluene (100 mL) was cooled to −78° C. and treated with 42 mL of DIBAL (1.0 M in CH2Cl2; 42 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched cautiously with saturated aqueous citric acid and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Chromatography of the residue over silica gel, eluting with 3:2 hexane:EtOAc, gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2ccc(C)nc2)c(OC)n1
Yield: 62 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (commercially available from Aldrich, 830 mg, 4.5 mmol) was dissolved in degassed n-PrOH (10 mL) and then 3-bromo-6-methylpyridine (600 mg, 3.5 mmol), Na2CO3 (956 mg, 9 mmol), PPh3 (90 mg, 0.35 mmol) and Pd(OAc)2 (78 mg, 0.35 mmol) were added. The suspension was stirred at reflux for 1.5 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by SCX cartridge washing with MeOH and then collecting the product with MeOH—NH4OH (95-5) to give 500 mg of the title compound (62% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:32]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([O:25][CH3:32])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:26][CH:27]=1
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Reaction time: 5 h
Yield: 50 %

Procedure:
(3S)-2-[(4-Chlorobenzylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.08 g) is dissolved in methanol (30 ml) and thereto is added dropwise thionyl chloride (0.94 ml) at -20° C. The mixture is stirred at 50°-60° C. for 5 hours and then distilled to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried, treated with active carbon and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give the title compound (1.08 g, 50%) as colorless needles, mp 181°-182° C. (decomp.).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C@:12]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH2:13][CH2:14][CH3:15])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[Cl:22][C:18]1[CH:17]=[C:16]([C@@:12]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:24]2)([O:11][CH2:10][CH2:9][OH:8])[CH2:13][CH2:14][CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: CCC[C@](OCCO[Si](C)(C)C(C)(C)C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCC[C@](OCCO)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (1.1 g, 2.1 mmol) in MeCN (5 mL), TBAF (1.1 g, 4.2 mmol) was added in portions at rt. The reaction mixture was stirred for 2-3 h at 50-60° C. The solvent was removed in vacuo to the crude product, which was purified by column chromatography to afford (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)butyl)piperidine-1-carboxylate (750 mg, 87%). 1H NMR (CDCl3, 400 MHz) δ 7.31 (s, 1H), 7.24 (m, 2H), 7.17 (m, 1H), 4.21-3.90 (m, 2H), 3.80 (m, 2H), 3.37 (m, 2H), 2.31 (m, 1H), 2.05 (m, 3H), 1.88 (m, 4H), 1.56 (m, 1H), 1.44 (s, 9H), 1.38-1.10 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]2[CH2:11][O:12][CH2:13][C:14](=O)[N:9]2[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:11]1[CH:10]2[CH:6]([CH2:4][OH:3])[CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12]1
Reactant: CCOC(=O)C1CCN2C(=O)COCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN2CCOCC12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 69 (1.1 g, 5.0 mmol) in 50 ml of anhydrous THF are added LAH (400 mg, 10 mmol) and the mixture refluxed for 18 hours. The mixture is cooled to 0° C. and treated successively with 0.4 ml of water, 0.4 ml of 3N aq. sodium hydroxide, and 1.2 ml of water. The mixture is stirred for 15 min. and then extracted three times with DCM. The combined organic phases are dried over anhydrous sodium sulphate and evaporated. The residual yellow oil (880 mg) is purified by chromatography (Silica gel 60, 0.063-0.2 mesh, DCM/MeOH/conc. ammonia 90:9:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-trifluoromethylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 447 ([M+H]+); Anal. Calcd for C23H12F6N2O: C, 61.89; H, 2.71; N, 6.28. Found: C, 61.70; H, 2.66; N, 6.14.
Reaction SMILES: I[C:2]([F:6])=[C:3]([F:5])[F:4].I[C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.O=O>[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(COC)OC>[F:6][C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:2]([F:6])=[C:3]([F:5])[F:4])=[CH:10][CH:9]=1)=[C:3]([F:5])[F:4]
Reactant: Ic1ccc(I)cc1
Reactant: FC(F)=C(F)I
Agent: [Pd]
Agent: O=O
Agent: [Zn]
Solvent: COCCOC
Product: FC(F)=C(F)c1ccc(C(F)=C(F)F)cc1
Reaction time: 0.33 h
Yield: 65 %

Procedure:
A 5 liter 3-necked round bottom flask is fitted with a mechanical stirrer, a nitrogen padded reflux condenser and a rubber septum. Glyme (100 ml) and activated zinc granules (11.50 g, 0.18 mole) are added to the flask along with a magnetic stirring bar. The flask is then purged with nitrogen for 15 minutes, after which time iodotrifluoroethylene (20.3 g, 0.098 mole) is added slowly via syringe through the septum. After 20 minutes of stirring the mixture begins to turn brown and get warm. After 2 hours a white precipitate begins to form. After stirring is continued without heat for 4 hours, the flask is opened under a slow nitrogen purge and 1,4-diiodobenzene (16.0 g, 0.0485 mole) ia added along with palladium tetrakis(triphenylphosphine) (0.57 g, 0.00049 mole). The mixture is stirred overnight, resulting in the formation of a large amount of suspended solid. The reaction is allowed to stir an additional 24 hours, after which it is filtered, and the precipitate is washed with hexane (3 times with 50 ml each wash). The filtrates are combined and evaporated at 30° C. on a rotary evaporator to provide a residue which is purified by column chromatography (neutral alumina, hexane eluent) to give 7.50 g of CF2 =CF--Ph--CF=CF2 as product (0.0315 mole, 65% yield). This product is analysed by GC/MS and gives the following spectrum: m/e: 238 (100%); 188 (12.0%); 187 (46.4%); 169 (92.0%); 138 (18.8%); 99 (16.3%); 81 (12.3%); 69 (30.1%). The material is found to be air sensitive, fuming acid gasses if left exposed to oxygen.