Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:61])(=O)=O)=CC=1.CCCCC.[Li]CCCC>C1COCC1.CCOCC>[C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1[F:61])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Yield: 332.8 %

Procedure:
Compound 8 (0.48 kg) and NFSI (N-fluorobenzenesulfonimide) (0.29 kg) was dissolved in THF (3 L) and ether (1 L). To the solution was added 1.5 L of n-pentane, and the mixture was cooled to −78° C. in a dry-ice bath. A solution of n-BuLi in THF (2.5 M, 0.72 L) was added drop wise to the reaction mixture within 4 hours, while keeping the reaction temperature below −70° C. The reaction mixture was stirred another hour until HPLC indicated complete consumption of compound 8. Saturated ammonium chloride solution (aqueous, 2 L) was added drop wise to the reaction mixture. It was then allowed to warm to ambient temperature. Eight such reactions were combined and diluted with 30 L of ethyl acetate. The mixture was stirred for 30 minutes, then the organic phase separated and the aqueous layer was extracted with 20 L of ethyl acetate. The combined organic phase was washed with brine (10 L), dried over sodium sulfate, and concentrated to dryness. HPLC indicated ratio of compound 9 to its corresponding de-fluoro side product was about 3/1. The residue was loaded on a silica gel column (300˜400 mesh) and eluted with petroleum ether/dichloromethane/ethyl acetate (first 100/0/0, then 200/10/1 to remove the front impurities, then changed to 200/15/1 to collect the desired product 9, (then 200/20/1 to collect the side product). Altogether 1.38 kg of compound 9 (yield 36%, purity˜95%) was obtained. 1H-NMR (300 MHz, CDCl3) δ 7.25-7.92 (m, 25H), 5.04 (t, J=7.2 Hz, 1H), 4.45 (m, 1H), 4.33 (m, 1H), 3.98 (d, J=12.0 Hz, 1H), 3.86 (d, J=12.0 Hz, 1H), 1.55 (s, 3H), 1.48 (s, 3H), 1.18 (s, 9H); 13C-NMR DEPT-135 (75 MHz, CDCl3, δ<100) δ 78.70, 75.35, 71.10, 56.39, 28.04, 27.25, 26.82.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:17])([CH3:18])[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:32]5[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]5)=[O:25])=[CH:21][CH:20]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)O)cc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.137 mmol), 4-hydroxypiperidine (15 mg, 0.15 mmol), O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium hexafluorophosphate (HBTU) (57 mg, 0.15 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in 3 mL of anhydrous DMF was stirred at room temperature. The mixture was poured into 75 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as orange solid. Yield: 52 mg, 85%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH2:22][CH3:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1.[H-].[Na+].[H][H].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:36]([C:37]([O:39][CH3:40])=[O:38])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=4)=[C:16]([CH2:21][CH2:22][CH3:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: [H][H]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccccc1
Yield: 65.8 %

Procedure:
To a solution of 0.062 g (0.19 mmol) of the product of Step A in 1.5 mL of anhydrous DMF was added 8.4 mg of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere. After the reaction mixture had stirred 30 minutes at room temperature, hydrogen evolution had ceased, and a solution of 0.048 g of methyl 2-bromophenylacetate in 0.5 mL of dry DMF was added via syringe. The reaction mixture was stirred an additional 1.5 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered, evaporated and then chromatographed on a silica gel flash chromatography column eluted with 50% ethyl acetate-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 59 mg (66%) of the title compound as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(OC([N:21]1[CH:26]([C:27]2[CH:32]=CC=C[CH:28]=2)[CH2:25][C:24]2[NH:33][N:34]=[CH:35][C:23]=2[CH2:22]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH:26]([CH:27]([CH3:32])[CH3:28])[CH2:25][C:24]3[NH:33][N:34]=[CH:35][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1Cc2[nH]ncc2CN1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Benzyl 2-isopropyl-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using HPLC Method [2].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:7]=1)[O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[C:39]1[CH:38]=[CH:37][C:36]([O:35][CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH2:34][CH2:33]2)=[CH:44][CH:43]=1)#[N:10]
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCN)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3OCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
1.06 g (3.50 mmol) of 3-(2-aminoethoxy)-4-benzyloxybenzonitrile hydrochloride was dissolved in 15 ml of DMF. 1.23 g (3.84 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 710 mg (4.2 mmol)) of 2-chloro-1,3-dimethylimidazonium chloride and 1.45 ml (5.19 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]=1[C:7]([O:9]C(C)C)=[O:8])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)OC(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)O
Temperature: 70 °C
Yield: 8.1 %

Procedure:
To a stirred solution of Isopropyl 2-isopropoxy-6-pentadecylbenzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Isopropoxy-6-pentadecylbenzoic Acid (7.6 g, 80%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:34])=[C:17]([C:19]3[S:23][C:22]([S:24][CH3:25])=[C:21]([C:26]#[N:27])[C:20]=3[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:18]=2)[CH:9]=[CH:10][CH:11]=1.CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>C(Cl)Cl>[C:26]([C:21]1[C:20]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:19]([C:17]2[CH:18]=[C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=3)[O:5][CH2:4][CH2:3][CH2:2][O:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:14]=[CH:15][C:16]=2[CH3:34])[S:23][C:22]=1[S:24][CH3:25])#[N:27]
Reactant: CSc1sc(-c2cc(Nc3cccc(OCCCO)c3)ccc2C)c(-c2cccnc2)c1C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1sc(-c2cc(Nc3cccc(OCCCOS(C)(=O)=O)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-{5-[3-(3-hydroxy-propoxy)-phenylamino]-2-methyl-phenyl}-2-methylsulfanyl-4-pyridin-3-yl-thiophene-3-carbonitrile (370 mg, 0.76 mmol) in DCM (10 mL) was added Et3N (155 mg, 0.15 mmol) followed by MsCl (130 mg, 1.15 mmol). The resulting mixture was stirred at ambient temperature for 10 min under nitrogen then poured into 20 ml water and extracted with DCM (20 ml×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The desired product was obtained (391 mg, 91%) and confirmed by LC/MS (Calculated: 565.12; observed: 565.1+1, ES+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:36][CH2:37][CH3:38])=[C:16]([CH:22]4[CH2:25][N:24](C(OCC5C=CC=CC=5)=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.O>CO.[Pd]>[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:36][CH2:37][CH3:38])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[CH3:21])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (170 mg, 0.32 mmol, racemic intermediate) and 5% palladium (80 mg) were combined in methanol (12 mL), to which was added 0.25 M hydrogen chloride in water (3.2 mL, 0.79 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The suspension was filtered. The filtrate was neutralized with sat. NaHCO3 solution, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and filtered, concentrated to give the desired product (117 mg, 92%). LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2; Found: 401.1.
Reaction SMILES: B(F)(F)F.CCOCC.O[CH:11]([CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[N:19]([CH3:28])[C:17]1=[O:18].C[Si]([N:34]=[N+]=[N-])(C)C.C(OP(OCC)OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCC.O>[NH2:34][CH:11]([CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[N:19]([CH3:28])[C:17]1=[O:18]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: CCOP(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Solvent: CCCCC
Solvent: CCOCC
Solvent: O
Product: CC(N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 6 h
Yield: 50 %

Procedure:
The method described in Koziara and Zwierzak, Tetrahedron Letters 28:6513-6516,1987 was followed to make CT1520. Briefly, boron trifluoride etherate (0.06 mol) was added dropwise at 10°-30° C. to a stirred solution of 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (0.05 mol) and trimethylsilylazide (0.06 mol) in pentane (50 ml). After 24 hours at room temperature the mixture was poured into 100 mls of water. The organic phase was separated, washed with a 10% solution of sodium bicarbonate, and dried over sodium sulfate. The solution of the azide in pentane was stirred at 25°-30° C., and 0.05 mol of triethylphosphite was added. Stirring was continued for 6 hours, and the solution was left at this temperature for 72 hours. Solvent was evaporated off and the iminophosphorane was dissolved in ethanol (15 mls) and treated with p-toluenesulfonic acid monohydrate (0.05 mol) and water (0.05 mol). The mixture was refluxed for eight hours, evaporated and the residue diluted with 100 mls of ether. The tosyl salt of the amine was precipitated out and was recovered by filtration. Then, 30% aqueous ammonium hydroxide (20 mls) was added to the crystals and the free amine was extracted into dichloromethane (3×15 mls), dried over sodium sulfate and the solvent evaporated to yield the free amine as a viscous oil, 0.7 g with a 50% yield.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH3:1][S:2][CH2:3][C:4]([CH:5]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])=[O:13]
Reactant: CCOC(=O)CCCCI
Reactant: CSCC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(C(=O)CSC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl 4-(methylthio)-3-oxobutanoate (5.00 g) and potassium carbonate (3.72 g) in dimethylformamide (25 mL) was added ethyl 5-iodopentanoate (6.89 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-10:1) to give 1-tert-butyl 7-ethyl 2-[(methylthio)acetyl]heptanedioate as colorless oil (5.88 g).
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:16]#[N:17].C[Si](Cl)(C)C.[CH2:30]([Mg]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.CCN(CC)CC.CCOCC>[F:12][C:13]1[CH:14]=[C:15]([C:16]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)([NH2:17])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Brc1nccs1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1nccs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To an oven-dried round bottomed flask cooled at −78° C. under N2, was added anhydrous Et2O (15 mL) and nBuLi (1.6 M in hexanes, 2.5 mL, 4.0 mmol, 1 eq.) sequentially. An Et2O solution (3 mL) of 2-bromothiazole (0.66 g, 4.0 mmol) was added to the above solution at −78° C. dropwise. The resulting solution was stirred at −78° C. to −70° C. for 20 min. To the lightly pale yellow solution, was added 3-fluoro-5-trifluoromethyl-benzonitrile in THF (2 mL) dropwise at −78° C. The resulting mixture was stirred at −78 to −70° C. for 2.5 h. Pretreated TMSCl (10:1 v/v TMSCl:Et3N, then centrifuge at r.t. for 15 min, 0.51 mL of the clear solution, 1.01 eq) was added to the stirred mixture dropwise at −78° C. The resulting mixture was stirred at −78 to −60° C. for 15 min, then room temperature for 30 min, during which period the solution changed from dark brown to light tan. The reaction mixture was cooled back to −78° C., benzyl magnesium chloride (2.0 M in THF, 2.0 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 15 min, then gradually warmed up to room temperature for 1.5 h. The reaction mixture was quenched by adding sat'd NH4Cl and 1 N HCl, and stirred for 20 min. The resulting crude reaction mixture was extracted with EtOAc, washed with 1N NaOH, sat'd NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, came out 20% EtOAc) to give racemic 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(thiazol-2-yl)ethanamine as light brownish viscous oil (0.35 g, yield: 24%). LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=2.97 min 367.04 (M+H), 350.02 (M−NH3). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.78 (d, J=3.18 Hz, 1 H), 7.66 (s, 1 H), 7.52-7.61 (m, 1 H), 7.08-7.19 (m, 5 H), 6.82 (dd, J=7.6, 2.0 Hz, 2 H), 3.86 (d, J=13.2 Hz, 1 H), 3.35 (d, J=13.2 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])/[CH:6]=[C:7](\[CH2:9][CH2:10][CH2:11][CH3:12])/[CH2:8][P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[CH3:2]
Reactant: C=C(CCCC)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-hexanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed in a manner analogous to that described in Example 15 to 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester. Reaction of the 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1>C1COCC1>[Br:29][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[C:9]([C:12]#[N:13])=[CH:8][C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[CH:6]2
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C#N)c3c(Br)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.160 g, 0.58 mmol) with NBS (0.12 g, 0.70 mmol) in THF (10 mL) according to method C to yield 0.080 g (39%) of a yellow solid: mp 145–146° C.; 1H NMR (DMSO-d6): δ 3.83 (3H, s), 7.08 (2H, d, J=8.79 Hz), 7.42 (1H, d, J=8.79 Hz), 7.84 (2H, d, J=8.79 Hz), 8.04 (1H, d, J=8.79 Hz), 8.42 (1H, d, J=1.95 Hz), 8.53 (1H, d, J=1.95 Hz), 11.21 (1H, s); MS (ESI) m/z 354/356 (M+H+; MS (ESI) m/z 352/354 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.CC(C)=[O:20].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[O:9]=[C:7]1[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][O:4][C:3]([C:2]([OH:20])=[O:1])=[CH:8]1
Reactant: CC(C)=O
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reaction time: 2 h
Yield: 5 %

Procedure:
232 g (1 mol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one were put into a 10 1 stirring flask containing 6.61 of acetone and 400 ml of water. The clear solution was cooled to +5° C. by means of an ice-bath. While maintaining the temperature at +5° to 10° C., 640 ml of Jones Reagent (202 g CrO3, 600 ml water, 174 ml H2SO4) was added dropwise over a period of 1 hr. Stirring was continued for 2 hours without cooling. The reaction mixture was filtered through a glass frit and the dark-green residue washed with 500 ml of acetone. The filtrate was then evaporated until all of the acetone was removed. To the aqueous, partly crystalline product was added 1.2 1 of methanol, and this mixture was then heated to its boiling point. The resulting clear dark-green solution was placed in an ice-bath and the product allowed to crystallize. The crystalline product was filtered and washed with 500 ml of a cold solvent mixture consisting of 250 ml methanol +250 ml water and finally dried. Yield: 195 g=79%. From the mother liquor a further 5% of the product could be isolated.
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C=O)C>[Br:11][C:6]1[CH:7]=[C:8]([CH2:9][O:10][CH2:15][CH3:16])[C:3]([NH2:2])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)cc1CO
Reactant: CCI
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (2-amino-5-bromo-pyridin-3-yl)-methanol hydrobromide (Apollo, Cheshire, UK, 3.52 mmol) in DMF (15 ml) cooled with an ice-bath was treated with 55% NaH in oil (7.4 mmol) and the RM was stirred for 5 min at 0° C. and 30 min at rt, then was added iodoethane (3.87 mmol) and the RM was stirred for 1 h 15 min at rt. The RM was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a light yellow oil. (HPLC: tR 2.07 min (Method A); M+H=231, 233 MS-ES)