Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1>>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])[CH:26]=[CH:25][C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cccc2[nH]ccc12
Agent: Cl
Product: CN(Cc1cccc2[nH]ccc12)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 73.7 %

Procedure:
According to the procedure of Example 35g, (1H-indol-4-ylmethyl)-methyl-amine (223 mg, 1.39 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (359 mg, 1.41 mmol), were coupled to give crude product. Purification by column chromatography gave the title compound (369 mg, 73%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.20-11.14 (m, 1H), 10.65-10.62 (m, 1H), 8.38-8.32 (m, 1H), 8.08-7.99 (m, 1H), 7.59-7.53 (m, 1H), 7.37-7.21 (m, 3H), 7.09-7.03 (m, 1H), 6.89-6.76 (m, 1H), 6.51 (s, 1H), 5.06-4.88 (m, 2H), 3.04-2.83 (m, 5H), 2.56-2.52 (m, 2H); ESI MS m/z 361 [C21H20N4O2+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][O:23][CH:24]=[CH2:25].CO>O1CCOCC1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:25][CH2:24][O:23][CH:22]=[CH2:21])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=COCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
In a 300 mL three necked oven dried round bottom flask equipped with a magnetic stirrer, 25 g (0.145 mol) of 2-naphthoic acid and 24.07 g (0.17 mol) of potassium carbonate (K2CO3) were suspended in 100 ml of dioxane and the mixture stirred at room temperature for 1 hour, forming a thick slurry. 18.53 g (0.17 mol) of 2-chloroethylvinyl ether dissolved in 10 ml of dioxane was slowly added to the reaction mixture using a dropping funnel over a period of 1 hour and the reaction refluxed overnight for another 12 hours until a complete reaction was ascertained by thin layer chromatography (TLC) analysis (silica plates; eluant 1% (v/v) methanol in chloroform). The reaction was quenched by pouring the mixture slowly into 400 ml of 0.01% (v/v) hydrochloric acid (HCl) solution, the crude product was extracted into 300 ml of ethyl acetate, and the ethyl acetate extract was washed sequentially with water and brine to neutral pH. The ethyl acetate extracts were then dried over sodium sulfate, filtered and concentrated by rotary evaporation to afford 32 g (92% yield) of an amber oil which solidifies upon standing. The product was used without further purification. 1H NMR (500 MHz, Acetone-d6): δ 8.64 (s, 1H), 8.08 (d, 2H, 8 Hz), 7.89 (d, 2H, 8.5 Hz), 7.64-7.59 (q, 2H), 6.56-6.52 (d/d, 1H, 7 Hz), 5.58 (s, 1H), 4.60 (m, 2H), 4.49 (m, 2H), 2.30 (s, 3H), 1.90 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 166.6, 151.5, 135.6, 132.4, 131.3, 129.4, 128.3, 128.1, 127.7, 127.0, 126.6, 125.2, 87.1, 65.9, 63.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[CH3:11][N:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([B:8]2[O:10][CH2:17][CH2:16][N:12]([CH3:11])[CH2:13][CH2:14][O:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: CN(CCO)CCO
Solvent: Cc1ccccc1
Product: CN1CCOB(c2cncc(Br)c2)OCC1
Temperature: 23 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
Step 1) A mixture of 3-bromopyridine-5-boronic acid [CAS-no. 452972-09-7] (10 g, 50 mmol) and N-methyldiethanolamine (5.9 g, 50 mmol) in toluene (50 mL) was stirred at 23° C. for 24 h, then totally evaporated, triturated with heptane to give 2-(5-bromo-pyridin-3-yl)-6-methyl-[1,3,6,2]dioxazaborocane (14.1 g, 100%) as an off-white solid. MS (ISP) 285.0 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)[CH:4]=1>Cl.O1CCOCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.3 %

Procedure:
tert-Butyl 4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridine-1′(2′H)-carboxylate (380.0 mg, 1.157 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (12.0 mL) to form a light yellow clear (then cloudy) solution. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo to afford 389 mg of product as a yellow gum. LC-MS calculated for C11H11F3N2: (M+H) 229; found 229.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:11][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9]1.[Br:31][C:32]1[N:37]=[C:36]([C:38]([OH:40])=O)[C:35]([NH2:41])=[CH:34][CH:33]=1>>[NH2:41][C:35]1[C:36]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH2:11][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:9]2)=[O:40])=[N:37][C:32]([Br:31])=[CH:33][CH:34]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, cis (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-5-((tert-butyldimethylsilyloxy)methyl)piperidin-3-ylcarbamate and 6-bromo-3-aminopicolinic acid were coupled. Following purification by RP HPLC the product fractions were allowed to stand at it overnight in the 0.1% TFA acetonitrile/water solution which removed the silyl group. Upon subsequent lyophilization, cis (+/−)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-5-(hydroxymethyl)piperidin-3-ylcarbamate was obtained and used in Suzuki reactions directly. LCMS (m/z): 521.0/523.1 (MH+); LC Rt=2.58 min.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[C:8]2[C:9](=[C:10]([CH3:12])[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]=2[OH:23])[S:13][N:14]=1
Reactant: CCOC(=O)c1nc(C)c2snc(-c3ccccc3F)c2c1O
Reactant: NCC(=O)O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccccc3F)nsc12

Procedure:
The title compound was synthesized in analogy Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-7-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 333.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH:23]([CH3:25])[CH3:24])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:12][C@H:13]([C@@H:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:32](Cl)(=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>C1COCC1>[CH3:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:1][C@@H:2]([CH:23]([CH3:25])[CH3:24])[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][C@H:6]2[C:10]([NH:12][C@H:13]([C@@H:17]([OH:22])[C:18]([F:21])([F:19])[F:20])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:4])=[O:41])=[CH:34][CH:35]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F)C(C)C)cc1
Temperature: -5 °C

Procedure:
Compound C was suspended in THF (350 ml) and powdered sodium carbonate (18.5 g) was added. The mixture was cooled to -5° C. and a solution of anisoyl chloride (11.9 g) in THF (50 ml) was added with stirring. The reaction mixture was stirred an additional 2 hours at 0° C. and then allowed to rise to ambient temperature. The reaction mixture was filtered and the filtrate acidified with 1M hydrochloric acid solution (20 ml) and washed with water. The aqueous layer was extracted with twice with diethyl ether and the combined organic layers washed with 50% saturated sodium bicarbonate solution, brine and dried. Solvent was removed by evaporation to give a colourless foam. The foam was triturated with diethyl ether and the resulting solid was collected by filtration and dried under vacuum at 40° C. for 3 hours to give (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[(S)-2-methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide as a white solid, m.p. 168°-170° C.; NMR (300 MHz, d6 -DMSO): 0.82-1.05 (m, 12H), 1.65-2.05 (3m, 5H), 2.05-2.25 (m, 1H), 3.60 (m, 1H), 3.82 (s, 3H+t, 1H), 3.93 (m, 1H), 4.12 (m, 1H), 4.45 (m, 2H), 6.45 (d, 1H), 6.98 (d, 2H), 7.65 (d, 1H), 7.90 (d, 2H), 8.35 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][CH:11]=[CH:12][C:13](Cl)=[O:14].CCN(CC)CC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=[CH:31][CH2:32][NH:33][C:13](=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:28][CH:29]=1
Reactant: O=C(Cl)C=CC=Cc1ccc(Cl)cc1Cl
Reactant: NCC=Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=CC=Cc1ccc(Cl)cc1Cl)NCC=Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride (62.5 mmol) in 300 mL CH2Cl2 at 0° C. was added Et3N (13.0 mL) followed by DMAP (i.e., 4-diaminomethylpyridine) (760 mg). To this was added a solution of 3-(4-chloro-phenyl)-allylamine (10.5 g) in 30 mL CH2Cl2. The mixture was stirred at 0° C. for 1 hr. Then 2 mL of MeOH was added, and the solution was stirred for 10 min. The solution was then diluted with aq. NaHCO3 and extracted with EtOAc. Filtration of solids and concentration of EtOAc layers provided a combined yield of 24.6 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-amide. MS: m/e 392.2 (MH+)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)nc23)C(C)(C)C1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
To a solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (170 mg, 0.617 mmol) and (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (144 mg, 0.633 mmol) in DMF (1543 μl) was added DIEA (237 μl, 1.358 mmol). The reaction was heated at 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate (100 ml). The ethyl acetate layer was washed with water (3×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified via flash chromatography (ISCO silica gel column, 0-10% MeOH-DCM) to afford (R)-tert-butyl 4-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (255 mg, 0.546 mmol, 88% yield) as a faint yellow solid. ESI-MS (analytical LCMS Method A): m/z 467.0 ([M+H]+). HPLC (analytical HPLC Method A) Rt: 3.413 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3OC)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxypropan-1-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.88 (m, 3H) 3.25 (s, 5 H) 3.96 (s, 5 H) 7.33-7.56 (m, 3 H) 8.31-8.56 (m, 1 H) 8.70 (br. s., 1 H) 8.91 (s, 1 H). MS m/z [M+H]+ 408.4.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[C:1]1([S:7][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCCSc1ccccc1
Yield: 99.5 %

Procedure:
Thiophenol (3 g), potassium carbonate (5.64 g) and 1,6-dibromohexane (6.64 g) were reacted and treated in the same manner as in Preparation Example 99 to give 7.4 g of 6-phenylthiohexyl bromide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1)=[O:11].[CH2:18]([N:25]([CH2:31]OC)[CH2:26][Si](C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:8][O:9][C:10]([C@@:12]12[CH2:31][N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C@@H:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)C1=CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)[C@]12CCCC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclohexene-1-carboxylic acid methyl ester (25.0 g, 178 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (46.6 g, 196 mmol) in 1,2-dichloroethane (178 mL) at room temperature, and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution (200 mL) was added to the reaction solution, followed by extraction with chloroform (150 mL×1, 100 mL×1). The organic layer was washed with brine (450 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→85:15→75:25) to give 21.3 g of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].IC.[CH3:40]COC(C)=O>CN(C=O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[N:27]([CH3:40])[CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(C)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1C#N
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 9.14 mg) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D9) (120 mg) in dry DMF (5 mL) at RT. After stirring for 5 min, iodomethane (0.032 mL) was added. The resulting solution was stirred at RT for 15 min, then 1 hour more. EtOAc (50 mL) was added and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (50 mL), followed by water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D10) (60 mg) as a pale yellow oil. MS (ES): C28H30N4O4 requires 486; found 487.0 (M+H+).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C[O-].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.C(OC(C1C=C(C[C@H](NC(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)C(O)=O)C=CC=1OCC(OCC)=O)=O)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)N=C=NC(C)C
Agent: CCOC(=O)COc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1C(=O)OCC
Solvent: CN(C)C=O
Product: COc1ccccc1C=O
Reaction time: 9.5 h

Procedure:
The production of this library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme I). The AMEBA resin was then treated with the corresponding amine and NaBH(OAc)3 to give the corresponding reductive amination product. The tyrosine scaffold (5) was then coupled to the various amine resins using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1:1). The resin was then plated in a 96 well Robbins block then coupled to the corresponding acid with DIC and HOBT in DMF. The diethyl ester was hydrolyzed with excess LiOH in THF: MeOH (1:1) for 5-14 h at rt to yield the dicarboxylic acid on resin. The use of THF: MeOH (1:1) is crucial for this hydrolysis. The use of excess LiOH and neat MeOH, THF and DMF failed to yield the diacid. The product was then cleaved from the resin with 20% TFA/CH2Cl2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.[O-]CC.[Na+]>CCO.CCOC(C)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[CH:23]=[CH:24]2)[CH:7]=1
Reactant: Oc1ccnc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C

Procedure:
A mixture of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (see Example 1) (0.21 g) and 4-hydroxyquinoline (0.105 g) and sodium ethoxide (21 wt. % in EtOH) in 4 mL anhydrous EtOH was heated at 85° C. for 6 hours, cooled to room temperature, diluted with EtOAc and acetic acid, washed with water and brine, and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue which was purified with flash silica gel using EtOAc as the eluent. Concentration in vacuo of the product-rich fractions provided the title compound, m.p. 170° C.-172° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:15])[CH2:10][CH2:9]2.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:27][C:28]([F:34])([F:33])[CH2:29][C:30]([NH:15][CH:11]1[C:12]2[C:8](=[CH:7][C:6](/[CH:5]=[CH:4]/[CH:3]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)[C:2]([F:1])([F:25])[F:26])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[O:31]
Reactant: O=C(O)CC(F)(F)F
Reactant: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(F)(F)F)NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Yield: 53.3 %

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC.HCl (0.038 g, 0.35 mmol), HOBt.H2O (0.07 g, 0.46 mmol) and DIPEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH2:19])=[CH:11][CH2:10]1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([O:21][CH3:20])=[O:32])=[CH:24][CH:25]=2)=[O:30])=[CH:11][CH2:10]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of Example 12C (33 mg, 0.11 mmol) in CH2Cl2 (1 mL), 4-chlorocarbonyl-benzoic acid methyl ester (33 mg, 0.16 mmol) and diisopropylethyl amine (0.05 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (41 mg, 81%). 1H NMR (500 MHz, CDCL3) δ ppm 8.06-8.10 (m, 2H), 7.86-7.92 (m, 2H), 7.37-7.41 (m, 1H), 7.15-7.26 (m, 2H), 5.73-5.82 (m, 1H), 5.02-5.13 (m, 1H), 4.01-4.13 (m, 3H), 2.50-2.95 (m, 3H). MS (ESI) m/z 463 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.ClS([N:25]=[C:26]=[O:27])(=O)=O.O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[C:26]([NH2:25])=[O:27])[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1c(O)cc2oc3cc(Cl)c(C(N)=O)n3c(=O)c2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To 100 mg (0.34 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 10 mL of toluene and 15 mL of CH2Cl2 was added 0.03 mL (0.34 mmol) of chlorosulfonylisocyanate at 0° C. After 15 min., the mixture was warmed to RT, stirred for 30 min., and then 2 mL of water was added. After 30 min, the solids were filtered, washed with ether and dried in vacuo to give 60 mg of the title compound: mp 250° C. dec.