Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][N:34]=[C:35]=[O:36])[CH3:29]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][NH:34][C:35]([NH:17][C:15]1[S:16][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=2)=[C:13]([CH3:18])[N:14]=1)=[O:36])[CH3:29]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1cccc(S(C)(=O)=O)c1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2cccc(S(C)(=O)=O)c2)s1
Temperature: 60 °C

Procedure:
A stirred suspension of 5-(3-methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide (176d) (0.172 g, 0.64 mmol) in DCM (15 ml) is treated with Hunigs base (0.45 ml, 2.36 mmol) followed by ethyl-3-isocyanatopropionate (0.092 g, 0.64 mmol). The reaction mixture is stirred and heated to 60° C. for 10 hours and then the solvent in removed in vacuo. The product is purified by chromatography on silica to give the titled compound
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][C:9]=2F)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:24][NH2:25]>>[CH2:15]([O:14][C:11]1[CH:10]=[C:9]2[C:8]([C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][NH:25]2)=[CH:13][CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1F)C1CCCC1
Reactant: NN
Solvent: O
Product: c1ccc(COc2ccc3c(C4CCCC4)n[nH]c3c2)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of cyclopentyl (4-benzyloxy-2-fluorophenyl)methanone (40 g, 0.13 mol) in hydrazine hydrate (50 ml) was refluxed overnight. After cooling to room temperature, the solid was filtered, dissolved in EtOAc, then washed with aqueous NH4Cl and brine. The solution was dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography (toluene/EtOAc 9/1) gave the expected product (13 g, 45% as solid).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=O)=[CH:30][C:25]=2[O:24][CH2:23]1.O>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:9][C:10]#[N:11])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (3.0 mL, 18.7 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 18.7 mL, 18.7 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of benzo[1,3]dioxol-5-yl-(4-methoxy-phenyl)-methanone (2.40 g crude, HPLC purity 93%, 9.4 mmol) in THF (15 mL) and refluxed for 3 hours. The reaction mixture was poured into water (80 mL), extracted with CH2Cl2 (2×60 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-benzo[1,3]dioxol-5-yl-3-(4-methoxy-phenyl)-acrylonitrile as an oil (1.98 g, 76% yield): 1H NMR (DMSO-d6) δ 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.10-6.13 (ms, 6H, 2CH2 and 2CH), 6.70-7.33 (m, 14H, Ar); 13C NMR (DMSO-d6) δ 55.3, 55.4, 93.0, 93.2, 101.6, 101.8, 107.8, 108.2, 108.3, 109.3, 113.9, 114.1, 118.6, 118.7, 123.6, 123.8, 129.3, 129.9, 130.4, 130.8, 130.9, 132.4, 147.3, 147.8, 148.4, 149.3, 160.3, 160.9, 161.0, 161.1. LC/MS showed desired peak at 280 for (M+1)+1 positive ion mass.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1.Cl[CH2:34][C:35](=[O:37])[CH3:36]>CC(N(C)C)=O>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:34][C:35](=[O:37])[CH3:36])=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Potassium carbonate (1.214 g, 8.79 mmol) was added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 46, preparation of starting materials) (1.07 g, 2.93 mmol) and 1-chloropropan-2-one (0.466 mL, 5.86 mmol) in DMA (10 mL). The resulting mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and diluted with water (25 mL) then extracted with DCM (2×25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)propan-2-one (1.190 g, 96%) as a gum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[CH2:31][O:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[C@H:32]([CH2:34][OH:35])[CH2:31][O:30][C:29]4=[O:28])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 57.9 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.6 g) described in Preparation Example 61 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (903 mg), the title compound (1 g) was obtained.
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4](OCOC)[C:3]=1[C:21](=[O:23])C>CO>[CH3:16][O:15][CH2:14][O:13][C:6]1[CH:7]=[CH:2][C:3]([CH:21]=[O:23])=[CH:4][CH:5]=1
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Solvent: CO
Product: COCOc1ccc(C=O)cc1
Yield: 100.1 %

Procedure:
In 30 ml of methanol were dissolved 14.73 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 13 and 7.55 g of the p-methoxymethoxybenzaldehyde obtained in Production Example 25, and a saturated solution of sodium hydroxide in methanol was added to the solution and the mixture was stirred at room temperature for 1 day to effect a reaction. After the reaction, the reaction mixture was carefully neutralized with dilute hydrochloric acid and extracted with 1.5 l of ethyl acetate, and the ethyl acetate layer was washed with water (500 ml×4 times), shaken with a saturated aqueous solution of sodium chloride (300 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation to obtain 18.94 g (yield=88.2%) of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:11][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:10])[CH:4]=1
Reactant: OCc1cc(C(F)(F)F)ccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of (4-trifluoromethyl-pyridin-2-yl)-methanol (290 mg, 1.64 mmol) in CH2Cl2 (15 mL) at room temperature was added Dess-Martin periodinane (764 mg, 1.8 mmol). The reaction mixture was stirred at room temperature for 1 h then quenched with saturated aqueous NaHCO3 (10 mL) and 10% aqueous Na2S2O3 (10 mL). The biphasic mixture was diluted with CH2Cl2 and stirred vigorously for 10 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated to give 300 mg of 4-trifluoromethyl-pyridine-2-carbaldehyde as a pale yellow oil which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm) 10.15 (s, 1H), 9.00 (d, J=5.3 Hz, 1H), 8.19 (s, 1H), 7.77 (dd, J=5.3, 1.3 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc(CCl)on1
Product: CCOP(=O)(Cc1cc(C)no1)OCC
Yield: 74 %

Procedure:
5-Chloromethyl-3-methylisoxazole (1.12 g) was dissolved in triethyl phosphite (2.0 ml) and heated at reflux for 1 h. The residue was then distilled under reduced pressure to give 5-diethylphosphonomethyl-3-methylisoxazole (1.47 g, 74%); bp 122°-5° C. at 0.5 mm; νmax (film) 2980, 2930, 2910, 1605, 1440, 1420, 1390, 1255, 1160, 1060-1010, 980, 900 cm-1 ; δH (CDCl3) 1.35 (3H, t, J=7 Hz, OCH2CH3), 2.30 (3H, s, CH3 -het), 3.30 (1H, d, JH-P =24 Hz, CH2 -P), 4.10 (2H, m, OCH2CH3), 6.05 (1H, d, J=3 Hz, CH-Het); δC (CDCl3) 11.4 (C5), 16.3, 16.4 (OCH2CH3), 24.6, 26.8 (C1), 62.7, 62.8 (OCH 2 CH3), 104.1, 104.2 (C3), 160.1 (C4), 163.5, 163.6 (C2); m/e (relative intensity) 233 (M+, 18%), 192 (47), 177 (41), 136 (50), 109 (100), 97 (82), 96 (35), 81 (76), 43 (32) (Found: 233.0831. C9H16NO4P requires 233.0816).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15].[C:17](=S)=[S:18].O>C1C=CC=CC=1>[SH:18][C:17]1[O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH:15]=1
Reactant: CC(=O)c1ccccc1O
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: O=c1cc(S)oc2ccccc12
Temperature: 15 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
Part A: Potassium t-butoxide (134 g, 1.2 mole) is covered with benzene (1 L) in a flame dried round bottom flask equipped with an overhead stirrer, addition funnel, thermometer, and a nitrogen inlet. This suspension is maintained at 15° C. A solution of o-hydroxyacetophenone (54.4 g, 48.1 ml, 0.4 mole) and carbon disulfide (30.4, 24 ml, 0.4 mole) in benzene (700 ml) is slowly added over 1.3 hours, applying an ice bath periodically in order to maintain the temperature 18° C. The slurry which forms is stirred at ambient temperature for one day. The reaction mixture is transferred to a separatory funnel containing water (4 L) and extracted with ether (4×250 ml) and EtOAc (3×250 ml). The aqueous layer is acidified with 10% H2SO4 (1 L) and stirred at ambient temperature overnight. The resulting solid is filtered off and dried in vacuo at 50° C. overnight to yield 22.07 g of 2-mercapto-4H-1-benzopyran-4-one. Mp 207°-8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:33][C:30]3[CH:29]=[CH:28][C:27]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[CH:32][CH:31]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncnc(Oc3ccc(-n4ccnc4)cc3)c2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 91.2 %

Procedure:
A mixture of 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester (63 mg, 0.2 mmol), 4-imidazol-1-yl-phenol (42 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol, 1 equivalent) in anhydrous DMF (1 ml) was heated to 90° C. overnight. The resulting residue was purified by Flash Chromatography (hexanes:ethyl acetate=1:1) to give 1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester [A1] as a yellow solid (80 mg, 92%). 1H NMR (CDCl3, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.38-7.42 (m, 2H), 7.46 (t, 1H), 7.55-7.59 (m, 3H), 8.17 (s, 1H), 8.90-8.92 (m, 1H). Exact mass calculated for C21H22N6O5 438.17, found 439.2 (MH+).
Reaction SMILES: [K].Br[C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].[OH-].[K+]>O.[Cu]>[CH3:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:3]1[C:4](=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: [Cu]
Agent: [K+]
Agent: [K]
Solvent: O
Product: COc1ccc(Nc2cc([N+](=O)[O-])ccc2C)c(C(=O)O)c1
Yield: 37.2 %

Procedure:
Potassium salt of 2-bromo-5-methoxybenzoic acid (23 g) and 2-methyl-5-nitroaniline (40 g) are stirred and heated at 110° C. in the presence of 50 mg of catalytic copper for 50 minutes. Next, the reaction mixture is poured on 5% solution of potassium hydroxide in water (600 ml) and cooled. The formed precipitate is filtered off, washed with water, and the collected solutions are acidified with hydrochloric acid to pH 5. The formed solid is filtered off and crystallized from methanol-acetone (2:1) to give N-(2′-methyl-5′-nitrophenyl)-5-methoxyanthranilic acid (11.2 g, 56% yield), m.p. 219-221° C. 1H NMR (d6 DMSO): δ9.20 (bs, 1H), 7.88 (d, 1 H, J=1.9 Hz), 7.65 (dd, 1 H, J1=7.8 Hz, J2=1.9 Hz), 7.44 (d, 1 H, J=8.3 Hz), 7.43 (d, 1 H, J=2.9 Hz), 7.26 (d, 1 H, J=8.8 Hz), 7.19 (dd, 1H, J1=8.8 Hz, J2=2.9 Hz), 3.68 (s, 3 H), 2.27 (s, 3 H).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=2[CH3:11])=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1C(F)(F)F
Reactant: COC(=O)c1c[nH]c(Br)c1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c(-c2ccc(Cl)cc2C(F)(F)F)c1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A mixture of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (0.44 g, 2.0 mmol), [4-chloro-2-(trifluoromethyl)phenyl]boronic acid (0.90 g, 4.0 mmol), Na2CO3 (0.64 g, 6.0 mmol) and palladium tetrakis(triphenylphosphine) (0.12 g, 0.10 mmol) in toluene/water (9:1, 10 ml) was stirred at 110° C. for 2.0 h under N2. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (dichloromethane) to give the title compound (0.41 g, 65%) as a pale yellow solid.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].C1CCC(NC2CCCCC2)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:64]([O:68][C:69]([N:71]1[CH2:75][CH:74]([O:76][C:77]2[CH:82]=[CH:81][C:80]([F:83])=[C:79]([F:84])[CH:78]=2)[CH:73]2[NH:85][CH2:86][CH2:87][CH:72]12)=[O:70])([CH3:67])([CH3:66])[CH3:65]>CN1C(=O)CCC1.CCOC(C)=O.CCOCC>[C:64]([O:68][C:69]([N:71]1[CH2:75][CH:74]([O:76][C:77]2[CH:82]=[CH:81][C:80]([F:83])=[C:79]([F:84])[CH:78]=2)[CH:73]2[N:85]([C:7](=[O:9])[CH:2]([NH:1][C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:86][CH2:87][CH:72]12)=[O:70])([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2NCCC21
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing Cbz-Tle-OH.DCHA salt (4.1 g, 9.0 mmol) and HATU (3.8 g, 10 mmol) in NMP (50 mL) was added NMM (1.5 mL), followed by a solution of crude 22 (2.6 g, 7.5 mmol) in NMP (50 mL) at room temperature. The reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with 10% EtOAc in Et2O, washed successively with water, 1N HCl, 1N NaOH, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by RP-HPLC (2″ Dynamax® C18; 10-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 3.5 g of 23 as white foam. Mass spectrum, m/z [688.3] (M+H)+.
Reaction SMILES: [CH:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>C(O)C.[Pd]>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC=Cc1cc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCc1cc2ccccc2[nH]1

Procedure:
2-Undec-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until the hydrogen gas consumption was completely stopped. The reaction mixture was filtered through celite. The solvent was evaporated to afford the desired product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([C:13](OCC)=[O:14])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.[O-2].[O-2].[Mn+4]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]=[O:14])[CH:7]=1
Reactant: CCOC(=O)c1cc(C2OCCO2)sc1CC
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1sc(C2OCCO2)cc1C=O
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of ethyl 5-(1,3-dioxolan-2-yl)-2-ethylthiophene-3-carboxylate (8.71 g) synthesized above in tetrahydrofuran (170 mL) was added lithium aluminum hydride (2.58 g) at 0° C., and the mixture was stirred for 1 hr. Water (5.20 mL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (5.20 mL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a colorless oil. To a solution of the obtained oil in tetrahydrofuran (150 mL) was added activated manganese dioxide (36.0 g), and the mixture was stirred at room temperature for 4.5 hr. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.36 g, 88%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:18])[CH:3]=1.FC1C=C([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[F:18][C:4]1[CH:3]=[C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: Fc1cc(Br)ccc1Nc1nc2ccccc2s1
Product: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)c(F)c2)OC1(C)C

Procedure:
N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine was prepared from N2-(4-bromo-2-fluorophenyl)-1,3-benzothiazol-2-amine (1.699 g, 5.258 mmol) in a manner similar to that used for N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.825 g, 42%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=14.48 min, 90%; m/z 371 (MH+).
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[CH3:17][O:18][C:19](=[O:51])[C:20]([CH3:50])([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:21][C:22]1[S:23][C:24]([CH:27](O)[CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:25][CH:26]=1.B(F)(F)F>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:51])[C:20]([CH3:50])([O:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:21][C:22]1[S:23][C:24]([CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:33][C:34]=2[CH3:35])=[CH:25][CH:26]=1
Reactant: COC(=O)C(C)(Cc1ccc(C(O)CCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(C)(Cc1ccc(CCCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of triethylsilane (0.62 mL, 3.89 mmol) in CH2Cl2 (4 mL) at −20° C., boron trifluoride diethyl etherate (0.49 mL, 3.89 mmol) was added. A solution of 3-{5-[1-hydroxy-3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-methyl-2-phenoxy-propionic acid methyl ester (650 mg, 1.30 mmol) in CH2Cl2 (4 mL) was then added dropwise to the BF3 solution over 1 h, keeping the temperature at −15° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with 1 N NaOH (approx. 3.6 mL) diluted with 1.8 mL of water and the pH was adjusted to pH 4.0 using 1 N HCl and 1 N NaOH. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×30 mL). The combined organic layers were then washed with 0.1 N HCl (30 mL) and water (2×30 mL). Xylene (15 mL) and NaCl were added and the organics were concentrated to dryness to yield a yellow oil. The product was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 2 H), 7.37 (m, 4H), 7.20 (m, 1 H), 6.96 (t, 1 H), 6.84 (d, 2 H), 6.60 (dd, 2 H), 3.72 (s, 3 H), 3.41 (d, 1 H), 3.30 (d, 1 H), 2.78 (t, 2 H), 2.50 (t, 2 H), 2.24 (s, 3 H), 2.00 (m, 2 H), 1.43 (s, 3 H); MS (EI) 476.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([C:23]([O:25]CC)=[O:24])[C:12]2=[O:28])=[CH:2]1.[OH-].[K+].Cl>C(O)C.O1CCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([C:23]([OH:25])=[O:24])[C:12]2=[O:28])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To a solution of the compound (0.050 g, 0.13 mmol) of Example 1 in ethanol (1.0 mL), 50% potassium hydroxide solution (0.5 mL, 0.13 mmol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol. The crude material was dissolved in water (0.5 mL) and tetrahydrofuran (0.5 mL), then 2M hydrochloric acid (0.023 mL, 0.046 mmol) was added and the mixture was stirred for 30 min. The precipitate was collected by filtration, washed with water and diethyl ether then dried to afford the titled compound (0.012 g, y. 26%).