Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:24]Cl>C(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([Cl:24])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CN1c2ccccc2CC(Cl)c2ccccc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
50 ml of CH2Cl2 and 5 g (0.0227 mols) of (I) are loaded into a 250 ml pyrex round-bottom flask, under nitrogen and stirring, then 2.4 g of Na2CO3 (0.045 mols) are added thereto. The mixture is cooled to 0-5° C., irradiated from the outside with a 300 watt halogen lamp while adding a 1:1 chlorine and nitrogen gaseous mixture with 6 ml/minute flow, for 3 hours, then nitrogen for 10 minutes at the same flow rate. The mixture is filtered at 30° C. and methylene chloride is evaporated off. The residue is taken up with 15 ml of hexane and 4 ml of ethyl acetate, refluxed for 15 minutes, then cooled to 0° C. for 2 hours. The solid residue is recrystallized twice with the same solvent, to obtain 2.5 g (43% yield) of 5-cyano-10-chloro-10,11-dihydro-5H-dibenz[b,f]azepine (III) with melting point 139-140° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(=O)(O)[O-].[Na+].O.[CH3:16][O:17][C:18](=[O:38])[C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]([CH3:34])=[CH:21][C:20]=1[O:35][CH2:36][CH3:37]>O1CCOCC1.C(OCC)(=O)C.[Pd](Cl)Cl.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>[CH3:16][O:17][C:18](=[O:38])[C:19]1[CH:24]=[C:23]([C:4]2[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH2:1])[N:3]=2)[C:22]([CH3:34])=[CH:21][C:20]=1[O:35][CH2:36][CH3:37]
Reactant: CCOc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OC
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
2-Amino-4,6-dichloropyrimidine (246 mg, 1.5 mmol), bis(triphenylphosphine) palladium dichloride (53 mg, 0.07 mmol), sodium bicarbonate (252 mg, 3.0 mmol), 1,4-dioxane (2.5 ml), and water (1.5 ml) were placed in a reaction vessel. The resulting mixture was stirred at 80° C. for 10 minutes. To this mixture, 2-Ethoxy-4-methyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid methyl ester (320 mg, 1.0 mmol) obtained in Step 4 above was added dropwise after dissolving in 1,4-dioxane (2.5 ml). The resulting mixture was stirred at 80° C. for 20 hours. The reaction solution was diluted with ethyl acetate (100 ml), and washed three times with water (40 ml), and then with a saturated aqueous sodium chloride solution (40 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to yield 5-(2-amino-6-chloropyrimidin-4-yl)-2-ethoxy-4-methylbenzoic acid methyl ester (Compound 1-3) (210 mg) as a yellow solid material.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 93.8 %

Procedure:
Following a procedure similar to that described in Example 74(b), but using 4.03 g of 2-butyl-4-pivaloyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (a) above] and 0.22 g of sodium borohydride, 3.79 g of the title compound was obtained as crystals, melting at 134°-135° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[CH2:43][CH2:42][N:41]([C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH2:40][CH2:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCN(Cc3ccccc3)CC1)O2
Yield: 68.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 506 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.02 mmol), 365 mg CDI (2.25 mmol) and 386 mg 1-benzylpiperazine (2.2 mmol) yielded 568 mg of (4-benzylpiperazin-1-yl)(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methanone as a white powder.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:13][C:14](OCC)=[O:15])(=O)[CH2:10][CH3:11].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>>[CH2:10]([C:9]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:14](=[O:15])[CH:13]=1)[CH3:11]
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
Resorcinol (1.21 g, 11.0 mmol) was dissolved in hot ethyl propionylacetate (1.52 g, 10.0 mmol). To this stirred mixture at ice-water temperature was added dropwise a mixture of trifluoroacetic acid (1.70 mL, 22.0 mmol) and concentrated sulphuric acid (2.2 mL, 22.0 mmol) at such a rate that the reaction temperature was kept below 10° C. (about 30 min). The reaction mixture was then allowed to warm to room temperature and thereupon stirred for an additional 3 h before being quenched cautiously with ice-water. After stirring the suspension that formed for 1 h, the bright yellow precipitate was collected by suction filtration, washed exhaustively with water and then re-dissolved into acetone. The resulting solution was heated with activated charcoal, filtered and evaporated to give a light orange residue which was dried azeotropically with isopropyl alcohol. The crude product that obtained was purified by recrystallization from acetone/hexane (2:3) to give 3 as creamy crystals (806 mg, 4.24 mmol, 42%); mp 175-178° C. [Lit. [68] 177° C. (ethanol)]; δH (400 MHz, DMSO-d6) 1.22 (3H, t, J=7.3 Hz, CH3), 2.77 (2H, q, J=7.3 Hz, CH2), 6.09 (1H, s, C3-H), 6.71 (1H, d, JC6-H, C8-H=2.4 Hz, C8-H), 6.80 (1H, dd, JC8-H, C6-H=2.4 Hz and JC5-H, C6-H=8.4 Hz, C6-H), 7.64 (1H, d, JC6-H, C5-H=8.8 Hz, C5-H) and 10.53 (1H, s, exchanged with D2O, OH); MS (FAB+) m/z (rel. intensity) 190.8[100, (M+H)+]; MS (FAB−) m/z (rel. intensity) 342.8[60, (M−H+NBA)−], 188.8[100, (M−H)−]. Found: C, 69.4; H, 5.35; C11H10O3 requires C, 69.43; H, 5.30%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:26])[CH3:22]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C

Procedure:
To a stirred mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 25.8 mmol) and Cesium carbonate (12.6 g, 38.7 mmol) in dry DMF (50 ml) was added 2-Bromo-2-methyl-propionic acid ethyl ester (5.5 g, 28.2 mmol). The reaction mixture was heated at 90° C. under N2 for 18 h, before being allowed to cool to room temperature. The mixture was partitioned between EtOAc and H2O, the organic layer separated and washed with H2O (×2) and brine (×1), dried (Na2SO4), filtered and the solvent removed in vacuo. This afforded the crude product as a yellow oil, which was used directly in the next step (4.7 g, 15.3 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16].Cl>N1C=CC=CC=1>[I:11][C:4]1[S:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[C:13]([Cl:12])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1nc(C(F)(F)F)c(I)s1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Yield: 70.8 %

Procedure:
2-Amino-5-iodo-4-trifluoromethylthiazole (0.8 g) was dissolved in pyridine (3 ml) and 2,6-dichlorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 1 day at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)-2,6-dichlorobenzamide (0.9 g), m. p. 157-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[NH4+].[N:25]#[C:26][S-:27].BrBr>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:23])=[CH:18][C:19]2[N:22]=[C:26]([NH2:25])[S:27][C:20]=2[CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3cc4sc(N)nc4cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (1.00 g, 3.18 mmol) was dissolved in AcOH (8.0 ml), to which was added NH4SCN (486 mg, 6.38 mmol) and the mixture cooled in an ice bath. Br2 (0.33 ml, 6.42 mmol) in AcOH (0.33 ml) was added dropwise with stirring. After addition was complete, the reaction mixture was stirred at room temperature. After one hour, more NH4SCN (1.0 g, 13.1 mmol) was added, followed by more Br2 (0.33 ml, 6.42 mmol) in AcOH (0.33 ml), dropwise with stirring. The reaction mixture was then heated to reflux for several minutes. Upon cooling to room temperature, solids were filtered and washed with AcOH, followed by H2O. The volume of the filtrate was reduced in vacuo and the pH adjusted to pH 9-10 with 1.0N NaOH. The resulting solids were filtered, washed with H2O, and dried under high vacuum to give 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (568 mg, 48%). 1H-NMR (400 MHz, DMSO): 8.45 (d, 1H), 7.82 (d, 1H), 7.73 (br s, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 6.44 (d, 1H), 3.94 (s, 6H). LC/MS Calcd for [M+H]+ 372.1. found 372.2
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[S:11]1[C:15]2[CH:16]=[C:17]([C:20]3([C:23]#N)[CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.C([OH:28])(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[S:11]1[C:15]2[CH:16]=[C:17]([C:20]3([CH:23]=[O:28])[CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: N#CC1(c2ccc3ncsc3c2)CC1
Reactant: CC(C)O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccc3ncsc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.00 M, 2.10 mL, 0.0021 mol) was slowly added to a solution of 1-(1,3-benzothiazol-6-yl)cyclopropanecarbonitrile (0.28 g, 0.0014 mol, prepared in Example 79, Steps 1-3) in toluene (2 mL) at −78° C. The mixture was slowly warmed to RT and stirred overnight. After cooling to −60° C., isopropyl alcohol (0.32 mL) was carefully added. The mixture was warmed to 0° C., and saturated potassium sodium tartrate (50 mL) was added, and stirred at RT for 30 min. The mixture was extracted with ethyl acetate (3×40 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with 40% ethyl acetate in hexanes to afford 1-(1,3-benzothiazol-6-yl)cyclopropanecarbaldehyde. Analytical LCMS: (M+H)+=204.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[S:18]1[CH2:22][CH2:21][NH:20][C:19]1=[S:23]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:20]2[CH2:21][CH2:22][S:18][C:19]2=[S:23])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: S=C1NCCS1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSC1=S
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (3.1 g) and tetrahydrofuran (50 ml) were added 1,3-thiazolidine-2-thione (2.0 g) and triethyl amine (2.5 g). The mixture was stirred at 50° C. for 30 minutes under nitrogen atmosphere. The reaction mixture was filtered and the solvent was removed at a reduced pressure. To the residue was added water, and the solution is extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried with use of Glauber's salt. The solvent was distilled off and the resulting crystals were purified by silica gel column chromatography (developer: dichloromethane) and recrystallized from dichloromethane to obtain 3.3 g of the desired compound as yellow needle crystals (yield 82.5%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[CH2:45][NH:46][C:47]([C:49]1[O:53][N:52]=[C:51]([NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH:50]=1)=[O:48]>C1COCC1>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[CH2:45][NH:46][C:47]([C:49]1[O:53][N:52]=[C:51]([N:54]([CH2:4][CH2:3][O:2][CH3:1])[C:55](=[O:60])[C:56]([F:58])([F:59])[F:57])[CH:50]=1)=[O:48]
Reactant: Cc1ccc(Cl)cc1CNC(=O)c1cc(NC(=O)C(F)(F)F)no1
Reactant: COCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN(C(=O)C(F)(F)F)c1cc(C(=O)NCc2cc(Cl)ccc2C)on1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
Into a round bottom flask was placed 2-methoxyethanol (89.1 μL, 1.13 mmol), and triphenylphosphine (0.296 g, 1.13 mmol) under an atmosphere of nitrogen in THF (4.7 mL). The solution was cooled to 0° C. and diisopropyl azodicarboxylate (0.238 mL, 1.21 mmol) was added dropwise. After stirring for 15 min, N-(5-chloro-2-methylbenzyl)-3-[(trifluoroacetyl)amino]isoxazole-5-carboxamide (0.292 g, 0.807 mmol) in THF (4.7 mL) was added to reaction flask. The ice bath was removed and the resulting solution was stirred at rt for 15 h. The reaction solution was diluted with 1 N HCl and ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (30% ethyl acetate/hexs) to give the desired product as a white solid (300 mg, 89%). LCMS calculated for C17H18ClF3N3O4(M+H)+: m/z=420.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:48][C:49]([CH3:51])=[CH2:50]>C1COCC1>[CH3:1][O:2][C:3](=[O:36])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[N:8]=[C:7]([N:21]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:6]=1)[CH2:50][C:49]([CH3:51])=[CH2:48]
Reactant: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of [2-[isobutyl-(4-trifluoromethyl-phenyl)-amino]-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (75 mg, 0.15 mmol) in THF (5 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 300 μL, 0.15 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (20 mg, 0.15 mmol) was added and stirred for an additional 30 minutes The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (0-30% methylene chloride in heptane) to give the product as a white solid (40 mg, 47%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.29 Hz, 2H), 7.71 (d, J=8.29 Hz, 2H), 7.57-7.68 (m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.19 (s, 1H), 6.55 (s, 1H), 4.61-4.79 (m, 2H), 3.96 (d, J=7.54 Hz, 2H), 3.67 (s, 3H), 2.68-2.85 (m, 1H), 2.31-2.47 (m, 1H), 2.07-2.26 (m, 1H), 1.70 (s, 3H), 0.89-1.05 (m, 6H). MS m/e 565.3 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])([CH3:33])[CH3:32])/[C:15]([NH:17][C@H:18]2[C@H:21]([CH2:22][CH3:23])[N:20]([S:24]([OH:27])(=[O:26])=[O:25])[C:19]2=[O:28])=[O:16])[N:13]=1.FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([C:34]([OH:36])=[O:35])([CH3:32])[CH3:33])/[C:15]([NH:17][C@H:18]2[C@H:21]([CH2:22][CH3:23])[N:20]([S:24]([OH:27])(=[O:26])=[O:25])[C:19]2=[O:28])=[O:16])[N:13]=1
Reactant: CC[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reaction time: 20 h
Yield: 25.6 %

Procedure:
250 mg of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are added at -10° C. to 3 ml of trifluoroacetic acid. After 20 hours at -10° C., the mixture is evaporated and the residue is purified by DCCC [droplet counter current chromatography; rising droplets in the mixture chloroform/methanol/water (7:13:8)]. 58 mg of amorphous (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.[Cu]I>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([CH2:10][N:11]5[CH2:15][CH2:14][CH2:13][CH2:12]5)=[N:7][C:6]=4[CH:16]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Ic1ccc2oc(CN3CCCC3)nc2c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4oc(CN5CCCC5)nc4c3)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A reaction mixture of 260 mg (0.792 mmol) 5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole, 171 mg (0.8 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine, 23 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium, 3.8 mg (0.02 mmol) CuI and 350 mg (1.075 mmol) Cs2CO3 in 10 mL THF is stirred for 14 h in an argon atmosphere at RT. Then the reaction mixture is evaporated down and the residue is purified by column chromatography on silica gel (DCM/MeOH 80:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([CH:30]([O:33][NH:34][S:35]([C:38]1[CH:46]=[CH:45][C:41]2[O:42][CH2:43][O:44][C:40]=2[CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH3:32])[CH3:29]>O1CCCC1>[O:42]1[C:41]2[CH:45]=[CH:46][C:38]([S:35]([N:34]([O:33][CH:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[CH2:19][C@@H:17]([OH:18])[C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)(=[O:36])=[O:37])=[CH:39][C:40]=2[O:44][CH2:43]1
Reactant: CCC(CC)ONS(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H]1CO1
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl (1S)-2-[4-(benzyloxy)phenyl]-1-[(2S)-oxiranyl]ethylcarbamate (2.66 g, 7.2 mmol) and the N-(1-ethylpropoxy)-1,3-benzodioxole-5-sulfonamide (2.30 g, 9.0 mmol) in tetrahydrofuran (12 mL) was added phosphazene base P4 tert-butyl solution (1.44 mL, 1.44 mmol, 1M in hexane). After stirring at ambient temperature for 18 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (100 mL), washed with 0.5 N hydrochloric acid (2×40 mL) followed by water (40 mL), saturated sodium bicarbonate (40 mL) and brine (40 mL), dried (magnesium sulfate) and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexane) to afford the title compound (4.25 g, 90%) as a white foam. 1H NMR (DMSO-d6): δ 0.79 (6H, dt), 1.11-1.74 (4H, m), 1.17 (9H, s), 2.37 (1H, t), 2.60-3.02 (3H, m), 3.38-3.49 (1H, m), 3.50-3.61 (1H, m), 4.03 (1H, m), 5.00 (2H, s), 5.04 (1H, d), 6.15 (2H, s), 6.60 (1H, d), 7.03 (2H, d), 7.10 (1H, d), 7.17-7.38 (9H, m)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([B:20]2[O:28][CH:27]3[C:22]([CH3:32])([CH:23]4[CH2:29][CH:25]([CH2:26]3)[C:24]4([CH3:31])[CH3:30])[O:21]2)[NH:15][Si](C)(C)C)[C:8]=1[O:33][CH3:34])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][C:41]([NH:43][CH2:44][CH:45]1[CH2:50][CH2:49][C:48](=[CH:51][C:52](O)=[O:53])[CH2:47][CH2:46]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:15][C:52](=[O:53])[CH:51]=[C:48]2[CH2:49][CH2:50][CH:45]([CH2:44][NH:43][C:41]([O:40][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:42])[CH2:46][CH2:47]2)[B:20]2[O:28][CH:27]3[C:22]([CH3:32])([CH:23]4[CH2:29][CH:25]([CH2:26]3)[C:24]4([CH3:31])[CH3:30])[O:21]2)[C:8]=1[O:33][CH3:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(CC(N[Si](C)(C)C)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC1CCC(=CC(=O)O)CC1
Product: COc1c(CC(NC(=O)C=C2CCC(CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C

Procedure:
Prepared from 2-Methoxy-3-[2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(trimethylsilanyl-amino)-ethyl]-benzoic acid tert-butyl ester and [4-(tert-Butoxycarbonylamino-methyl)-cyclohexylidene]-acetic acid following the procedure described in Step 1 of Example 1. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/hexane). ESI-MS m/z 681 (MH)+.