Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:47])[N:5]1[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:32][CH3:33])=[N:14][C:13]3[N:34]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[CH:35]=[CH:36][C:12]=3[C:6]1=[N:7]2.[OH-].[NH4+:49]>O1CCCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][C:6]2[C:12]3[CH:36]=[CH:35][N:34]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:38])=[O:39])[C:13]=3[N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:32][CH3:33])[N:5]=2)[C:3]=1[C:4]([NH2:49])=[O:47]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 8-fluoro-5-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (7.6 g, 11.6 mmol) in tetrahydrofuran (350 mL) was added 27% ammonium hydroxide (500 mL). The resulting biphasic mixture, was rapidly stirred for 24 hours, at which time no starting material was evident by TLC/LCMS. Three such reactions were combined, diluted with EtOAc, and the organic layers washed with saturated sodium chloride, dried over sodium sulfate, and taken to a residue under reduced pressure to give 2-fluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (19.3 g, 28.7 mmol, 80% Yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 8.04 (d, J=8.2 Hz, 1 H), 7.87-7.99 (m, 4 H), 7.79 (br. s., 2 H), 7.26-7.47 (m, 4 H), 6.87-7.06 (m, 1 H), 6.63 (d, J=2.4 Hz, 1 H), 6.47-6.58 (m, 2 H), 3.70-3.85 (m, 3 H), 3.05-3.19 (m, 4 H), 2.66 (quin, J=6.5 Hz, 1 H), 2.54-2.63 (m, 4 H), 2.32 (s, 3 H), 1.00 (d, J=6.6 Hz, 6 H). ESIMS (M+H)+=673.
Reaction SMILES: [C:1]1([CH:7]2O[C:8]2([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[CH3:10][C:9]1[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: CC(=O)C1(c2ccncc2)OC1c1ccccc1
Solvent: CCO
Product: Cc1n[nH]c(-c2ccccc2)c1-c1ccncc1
Yield: 34.4 %

Procedure:
Using the procedure of Example A-1, step 3, a solution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated to reflux for 4 hours. The crude product was purified by chromatography (silica gel, 1:1 acetone/hexane). The product was recrystallized from ethyl acetate and hexane to give 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (81 mg, 35%) as a crystalline solid: m. p. 212-214° C. Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>[Pd].C1COCC1.C(O)C>[N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Methyl 3-[4-(azetidine-1-carbonyl)-2-chloro-phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 17) (372 mg, 0.81 mmol) was added to a suspension of 10% palladium on carbon (37 mg, catalytic) in THF (10 mL) and ethanol (10 mL) and the resulting mixture was stirred under an atmosphere of hydrogen for 16 hours. The suspension was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure to afford the product (309 mg, 90%). 1HNMR δ (300 MHz, CDCl3) 2.10-2.23 (m, 1H), 2.36 (quintet, 2H), 2.52-2.65 (m, 1H), 2.94 (s, 3H), 3.32-3.54 (m, 2H), 3.89 (s, 3H), 4.18-4.39 (m, 4H), 4.90 (t, 1H), 6.94 (s, 1H), 7.01 (d, 2H), 7.32 (s, 1H), 7.48 (s, 1H), 7.64 (d, 2H); m/z 425 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=[CH:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([C:4]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC=Cc1c(C(C)C)nn2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C(C)C)nn2ccccc12
Yield: 79.2 %

Procedure:
A solution of 2.0 g of the compound obtained in Example 38 in 20 ml of ethanol was stirred in a hydrogen atmosphere at atmospheric pressure and room temperature in the presence of 100 mg of 10% palladium-on-charcoal for an hour. The solution was filtered and concentrated to dryness in vacuo. The residue was subjected to silica gel column chromatography, eluted with dichloromethane to give 1.6 g (62%) of the desired compound as colorless needles, mp 41°-42° C.
Reaction SMILES: [C:1]([O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:15](O)(=O)C=C>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([O:4][Si:5]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:12]([CH3:14])[CH3:13])(=[O:3])[CH:2]=[CH2:15]
Reactant: C=CC(=O)O
Reactant: CC(=O)O[Si](C(C)C)(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
4 g of acetoxy-triisopropylsilane and 1.6 g of acrylic acid (ATOFINA Norsocryl AA®) in 100 ml of toluene and 1 mL of N,N-dimethylformamide are mixed and heated. Azeotropic distillation of acetic acid affords triisopropylsilyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl
Yield: 54 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (0.466 g, 0.749 mmol) prepared in Example 86b, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (0.191 g, 54%) as a colorless solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH2:13]([O:15][P:16]([O:17][CH2:18][CH3:19])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:20])[CH3:14]
Reactant: C=CCCCCCCCCCI
Reactant: CCOP(OCC)OCC
Product: C=CCCCCCCCCCP(=O)(OCC)OCC

Procedure:
A first generation FP probe, FP-biotin, possessed a linear decamethylene chain connecting its FP reactive group to 5-(biotinamido)-pentylamine through an amide bond (15). A variant of FP-biotin in which the agent's decamethylene chain was replaced by a more hydrophilic tetraethylene glycol linker was synthesized. Briefly, tetraethyleneglycol (1) was monosilyated to provide compound 2, which following conversion to alkyl iodide 3, was reacted with triethylphosphite to give phosphonate 4. Desilyation of 4 with HF-pyridine, followed by treatment with N,N-disuccinimidyl carbonate, provided NHS-carbonate 6. Compound 6 was converted to monoethoxy phosphonate acid 7 by treatment with oxalyl chloride followed by hydrolytic workup. Compound 7 was treated with DAST to give fluorophosphonate 8, which was then coupled to 5-(biotinamido)pentylamine (Pierce) to provide FP-peg-biotin (9).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:13][O:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([C:20]2[C:15]([O:14][CH3:13])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=1
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1cc(Br)cc(C(C)(C)C)c1
Yield: 57.9 %

Procedure:
step 1—A sealed tube containing 3,5-dibromo-tert-butylbenzene (1.00 g, 3.425 mmol, CASRN 129316-09-2), 37 (522 mg, 3.413 mmol), Pd(PPh3)4 (194 mg, 0.168 mmol) and Na2CO3 (942 mg, 8.888 mmol) and a mixture of MeOH/DCM (8/2 10 mL) was irradiated in a microwave synthesizer at 100° C. for 10 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 2% EtOAc) to afford 0.633 g (58%) of 3-(3-bromo-5-tert-butyl-phenyl)-2-methoxy-pyridine (122) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:30][NH:31][C:32](=[O:34])[CH3:33].CC(C)([O-])C.[Na+]>C1COCC1.CCOCC>[C:32]([NH:31][O:30][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])(=[O:34])[CH3:33]
Reactant: CC(=O)NO
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of Example 1A (150 mg, 0.35 mmol) and N-hydroxyacetamide (52.3 mg, 0.70 mmol) in THF (10 mL) was added sodium tert-butoxide (67.0 mg, 0.70 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ether and washed with brine. The aqueous phase was extracted with ether (2×20 mL), dried over MgSO4, and filtered. The mixture was concentrated under reduced pressure and the residue was purified by FC on SiO2 using an Analogix® Intelliflash280™ (eluted with Hexanes-EtOAc: 0-30%) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.19 (s, 9 H), 1.21 (m, 1 H), 1.37 (s, 1 H), 1.94 (s, 2 H), 1.97-2.11 (m, 1 H), 3.65-3.92 (m, 2 H), 3.99-4.33 (m, 2 H), 4.34-4.55 (m, 1 H), 6.82 (s, 1 H), 7.66 (dd, J=9.2, 2.4 Hz, 1 H), 8.34 (d, J=8.8 Hz, 1 H), 8.61 (d, J=2.4 Hz, 1 H); MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1.C[O-].[Na+]>CO>[C:1]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Cyclohexanone (96 mL, 0.926 mol) was added to a stirred mixture of indole-6-carboxylic acid (50.0 g, 0.335 mol) in methanol (920 mL) at 22° C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the desired product (80.9 g, 97.5% yield).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.Cl>C1C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH:9]([Cl:15])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)C1CCC(=O)C(Cl)C1

Procedure:
The compound 4-t-butylcyclohexanone, 154.3 grams, is dissolved in one liter of benzene to which a trace of ferric chloride is added. The mixture is heated and 148.5 grams of sulfuryl chloride is added dropwise in periodic increments. The reaction mixture is slowly heated to its reflux temperature and maintained at that temperature until no further evolution of hydrochloric acid is observed. The solvent is removed in vacuo and the residue dissolved in a small amount of heptane. The solution is passed through an alumina column and the eluate removed by evaporation under reduced presssure to yield 167.6 grams of crude 4-t-butyl-2-chlorocyclohexanone.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].[O:21]=[C:22]1[N:26]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:25](=[O:35])[CH:24]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[S:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:35])[CH:24]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:44][CH2:45][CH:46]([NH:5][CH2:6][C@H:7]([OH:8])[C:9]4[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=4)[CH2:47][CH2:48]3)=[CH:39][CH:38]=2)[S:23][C:22]1=[O:21])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
Acetic acid (0.12 mL, 2.16 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (266 mg, 1.08 mmol) (which was obtained in Example 10), tert-butyl 2-{2,4-dioxo-5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidin-3-yl}acetate (450 mg, 1.08 mmol) (which was obtained in Example 49), and DMF (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 5/1) to produce a yellow solid (480 mg, 68% yield); mp 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.50 (m, 11H), 1.81-1.85 (m, 2H), 2.60-2.80 (m, 4H), 2.85-2.9 (m, 4H), 3.40 (m, 1H), 3.60 (m, 1H), 4.20 (s, 2H), 4.50 (m, 1H), 5.04 (m, 1H), 6.80-6.87 (m, 3H), 7.02 (m, 1H), 7.08 (m, 2H), 7.20 (m, 1H); Anal. Calcd. for C30H40N4O8S2: C, 55.54; H, 6.21; N, 8.64. Found: C, 53.86; H, 6.11; N, 7.65.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]1([N:27]([CH2:26][C@H:13]2[CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:34])[F:35])=[CH:11][CH:10]=2)[C:45](=[O:47])[CH3:46])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNc2ccccc2)cc1)C(F)(F)F
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.130 g, 0.247 mmol, Example 203) in CH2Cl2 (3.0 mL) was added 4-dimethylaminopyridine (6.1 mg, 0.049 mmol), Hünig's base (0.129 mL, 0.742 mmol), and acetyl chloride (0.035 mL, 0.49 mmol, Aldrich, St. Louis, Mo.). The resulting mixture was stirred at room temperature for 30 min and then the solvent was removed in vacuo. The residue was purified by column chromatography (24 g of silica gel, 10% to 40% EtOAc in hexanes) to afford N-phenyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide (0.032 g) as a mixture of two isomers:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2Oc2nc3ccccc3s2)C1
Temperature: 135 °C
Yield: 83.2 %

Procedure:
A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), 2-chloro-benzothiazole (0.5 mmol), and K2CO3 (1 mmol) in CH3CN (3 mL) was heated at 120-150° C. via Microwave for 1 h. The mixture was cooled down and separated through PTLC providing 3-[2-(benzothiazol-2-yloxy)-5-chloro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (180 mg). The ester was re-dissolved into CH2Cl2 (20 mL), and CF3COOH (3 mL) was added. The mixture was stirred at 25° C. for 4 h. After concentration, the title compound was obtained (192 mg). MS (ESI): mass calcd. for C16H13ClN2O2S, 332.0; m/z found, 333.1 [M+H]+. 1H NMR (MeOD): 7.23-7.07 (m, 4H), 6.92-6.81 (m, 3H), 5.14-5.08 (m, 1H), 4.51 (dd, J=12.5, 6.6 Hz, 2H), 4.23 (dd, J=12.5, 5.0 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[CH2:4][S:3]1(=[O:15])=[O:14].CCOC(C)=O.[O:22]1[CH2:24][C@@H:23]1[CH2:25][NH:26][C:27](=[O:29])[CH3:28].FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O>[Pd].CC#N>[OH:22][C@H:23]([CH2:24][NH:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[S:3](=[O:15])(=[O:14])[CH2:4][C:5]=2[CH:10]=1)[CH2:25][NH:26][C:27](=[O:29])[CH3:28]
Reactant: CN1c2ccc([N+](=O)[O-])cc2CS1(=O)=O
Reactant: CC(=O)NC[C@H]1CO1
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)NC[C@H](O)CNc1ccc2c(c1)CS(=O)(=O)N2C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
The product of Step 1 (0.20 g, 0.88 mmol) is dissolved into EtOAc (30 mL) in a Parr bottle and 10% Pd/C (100 mg) added under nitrogen. The mixture is hydrogenated on a Parr apparatus for 2 hrs at 30 psi. Filtration and evaporation of solvent gave a white solid. This material is added to a mixture of N-[(2S)oxiranylmethyl] acetamide (0.81 g, 7.0 mmol) and magnesium trifluoromethanesulfonate (0.42 g, 1.3 mmol) in dry CH3CN (10 mL) at room temperature. After 20 hrs solvent is evaporated and the residue purified by chromatography (4%MeOH/CH2Cl2) to give a foamy solid (0.23 g, 79%). HRMS (FAB) calcd for C13H19N3O4S +H1 314.1174, found 314.1174.
Reaction SMILES: Cl[CH2:2][CH2:3][Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[N:14]([CH2:2][CH2:3][Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[N+:15]=[N-:16]
Reactant: CCO[Si](CCCl)(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[Si](CCN=[N+]=[N-])(OCC)OCC

Procedure:
1.0 mole of 2-chloroethyltriethoxysilane and 1.1 moles of sodium azide in 500 ml of acetone were heated in the presence of 3 mole percent of the catalyst described in Example 1 (a) for ten hours under intensive stirring and under reflux. After separation of the salt the subsequent distillation under reduced pressure gave the 2-azidoethyltriethoxysilane in a yield of 69 weight percent with the following characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 35) (500 mg, 0.84 mmol) in dimethylformamide (7.0 ml) is added bis(triphenylphosphine)palladium(II)chloride (117.3 mg, 0.17 mmol), ethyl acrylate (457.2 μl, 4.18 mmol) and triethylamine (232.9 μl, 1.67 mmol). The reaction is stirred overnight (16 h) at 120° C., then cooled to room temperature, diluted with dimethylformamide (8 ml) and purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The title compound, which is still slightly impure, is isolated (356 mg) and then chromatographed again over silica gel 60 with cyclohexane/ethyl acetate (5:1) as eluent.