Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](Cl)=[O:12])=[C:9]([CH3:14])[S:8][C:7]=2[CH:15]=1.[CH3:16][NH2:17]>C1COCC1>[CH3:16][NH:17][C:11]([C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][C:7]=2[S:8][C:9]=1[CH3:14])=[O:12]
Reactant: COc1ccc2c(C(=O)Cl)c(C)sc2c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)sc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of this crude 6-methoxy-2-methylbenzo[b]thiophene-3-carbonyl chloride in THF (50 ml) was combined with a 2.0 M solution of CH3NH2 in THF (20 ml, 40 mmole). The resultant reaction mixture was stirred at ambient temperature for 3 hours. The solvent was removed by concentration, in vacuo, and the residue obtained was partitioned between H2O (50 ml) and CH2Cl2 (50 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 0.8 g of an amber solid which was purified by silica gel chromatography. Elution with CH2Cl2: EtOAc (80:20) and evaporation of the appropriate fractions gave 693 mg (72%) of an off-white solid. 1H NMR (DMSO-d6) δ8.15 (1H, q, J=4.6 Hz), 7.62 (1H, d, J=8.9 Hz), 7.47 (1H, d, J=2.4 Hz), 6.97 (1H, dd, J=2.4, 8.9 Hz), 3.79 (3H, s, 2.80 (3H, d, J=4.6 Hz), 2.53 (3H, s). Anal. Calcd. for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95; S, 13.63. Found: C, 60.97; H, 5.56; N, 5.85; S, 13.44.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][N:22]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][C:15]([F:33])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:35][NH2:36]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:30])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[CH:20]2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][N:22]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ncnn2C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a solution of ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (160 mg, 0.35 mmol) in methanol (2 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was stirred at 25° C. for 10 hr. The mixture was filtered to obtain the title compound as a white solid (45 mg, yield 30%). LC-MS (ESI) m/z: 420 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.10 (s, 6H), 3.36 (s, 2H), 3.59 (s, 3H), 4.91-4.99 (m, 2H), 6.91-6.95 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.05-7.08 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.20-7.23 (d, J=8.0 Hz, 2H), 7.35-7.37 (d, J=8.0 Hz, 2H), 7.72 (s, 1H), 7.79 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>ClCCl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:39](=[O:40])[C:38]([C:30]2[CH:29]=[C:28]([C:27]([F:26])([F:44])[F:45])[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=2)([CH3:43])[CH3:42])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1ccccc1S(=O)(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of 233 mg (1.0 mmol) 2-aminophenyl phenyl sulfone and 0.25 ml (1.5 mmol) N-ethyldiisopropylamine in 2 ml dichloromethane was cooled in an ice bath and a solution of 350 mg (1.1 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml dichloromethane was added dropwise. The reaction mixture was stirred at room temperature overnight, evaporated and the residue was purified by flash chromatography to give 490 mg (95%) of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][C:16]([CH3:18])=[CH2:17])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:24](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:24][CH2:17][C:16]1([CH3:18])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]3)[CH2:15]1
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CCN2C=O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C)c2c(c3c1OC(C)(CI)C3)CCN2C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a suspension of 2,3-dihydro-5-hydroxy-6,7-dimethyl-4-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (4.91 g, 20.0 mmol) in dichloromethane (10 mL) and methanol (20 mL) was added calcium carbonate (2.60 g, 26.0 mmol), the mixture was ice-cooled, a solution of benzyltrimethylammonium dichloroiodate (7.66 g, 22.0 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and concentrated under reduced pressure. To the residue was added a solution of sodium hydrogen sulfite (2.50 g) in water (50 mL), and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5;1 then 2:1), and recrystallized from ethyl acetate-diisopropyl ether to obtain 4.34 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]([OH:42])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:30][CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:14]([CH2:25][CH:26]([OH:42])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:30][CH2:29]3)[N:15]=2)=[CH:18][C:19]=1[CH3:24]
Reactant: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CNCC3)ccc1Cl
Reaction time: 2 h
Yield: 100.4 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.26 g, 2.13 mmol) was dissolved in trifluoroacetic acid (3 mL) and CH2Cl2 (3 mL) and allowed to stir for 2 h. The reaction mixture was concentrated, taken up in EtOAc (50 mL) and washed with aqueous NaHCO3 (2×25 mL). The EtOAc layer was dried over Na2SO4 and concentrated to give 2-(4-{3-[3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (1.05 g, 99%) as a yellow foam. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.27. MS (electrospray): m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3): 9.8 (br s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 4.56 (br s, 1H), 4.12-4.32 (m, 4H), 2.98-3.51 (m, 13H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[Br:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH2:26][CH2:25][Br:24])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccc(O)c3ccccc23)oc2ccccc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1c(-c2ccc(OCCBr)c3ccccc23)oc2ccccc12

Procedure:
To a solution of 11.9 g. (0.039 mol.) of 3-acetyl-2-(4-hydroxynaphthyl)benzofuran in 400 ml. of 2-butanone was added 100 ml. (0.24 mol.) of 1,2-dibromoethane and 22 g. (0.16 mol.) of anhydrous potassium carbonate. The reaction mixture was refluxed for 8 hours, then the solvent was evaporated and the excess 1,2-dibromoethane was removed by distillation in vacuo. The residue was chromatographed on silica with 10% hexane in methylene chloride as eluant to give 3-acetyl-2-[4-(2-bromoethoxy)naphthyl]benzofuran, m.p. 115°-117°.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C@@:15]2([CH2:16][CH2:17][CH3:18])[C:10](=[CH:11][C:12](=[O:19])[CH2:13][CH2:14]2)[C:9]2[C:4]1=[CH:5][C:6]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[C:7]([Cl:21])[C:8]=2[Cl:20]>C(O)C.O.[OH-].[Na+]>[NH2:2][CH:3]1[C@@:15]2([CH2:16][CH2:17][CH3:18])[C:10](=[CH:11][C:12](=[O:19])[CH2:13][CH2:14]2)[C:9]2[C:4]1=[CH:5][C:6]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:7]([Cl:21])[C:8]=2[Cl:20]
Reactant: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Ethyl [(9-amino-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetate hydrochloride (497.5 mg, 0.002 mole) is dissolved in a mixture of ethanol (17 ml), water (3 ml) and 1N sodium hydroxide (5 ml). The mixture is stirred at 25° C. for 10 hours, evaporated to dryness in vacuo and the residue dissolved in water (20 ml) and carefully neutralized with hydrochloric acid to the isoelectric points whereby a precipitate separates. The product is removed by filtration, washed with water and dried to give [(9-amino-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>O1CCOCC1.C(O)CCC>[C:44]([N:41]1[CH2:40][CH2:39][N:38]([C:35]2[CH:36]=[CH:37][C:32]([NH:31][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([NH2:27])=[O:26])[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:12])=[O:13])[C:6]=4[N:7]=3)=[CH:33][CH:34]=2)[CH2:43][CH2:42]1)(=[O:46])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(C(N)=O)c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(C(N)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 33.7 %

Procedure:
A mixture of 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (85 mg, 0.19 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (105 mg, 0.480 mmol) and trimethylsilyl chloride (0.030 mL, 0.24 mmol) in dioxane (1 mL) and nBuOH (1 mL) was stirred at 110° C. for 72 h. It was concentrated in vacuo. The residue was purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (40 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[C:23]([OH:25])=O.C(Cl)Cl.[NH2:29][C@H:30]([C:34]([OH:36])=[O:35])[CH:31]([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[C:23]([NH:29][C@H:30]([C:34]([OH:36])=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:25]
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Reactant: CC(C)[C@H](N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](C(=O)O)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
DMAP (367 mg, 3.0 mmol) and EDAC (748 mg, 3.9 mmol) were added as solids to a solution of 1,3-dimethylindole-2-carboxylic acid (568 mg, 3.3 mmol) in DMF (5 mL), and the resultant mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of the methyl ester of valine (553 mg, 3.3 mmol, in 5 mL of methylene chloride) was added to the mixture, and the mixture was first stirred for one hour at 0° C. then for 5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate washes were in turn washed with 5% KHSO4 solution saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give the title product as a yellow syrup (900 mg).
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: CC(=O)O[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=CC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
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: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.Cl.Cl.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:48][CH2:47][C:43]1[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=1)=[O:5]
Reactant: Cn1ccnc1CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1ccnc1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 1.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), C-(1-methyl-1H-imidazol-2-yl)-methylamine dihydrochloride (13.91 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((1-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (4.9 mg, 0.001 mmol, 13% yield): LCMS=525.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.24 (2 H, m), 7.70 (4 H, t, J=8.03 Hz), 7.52-7.64 (3 H, m), 7.00 (1 H, d, J=1.25 Hz), 6.88 (1 H, d, J=1.51 Hz), 5.18 (1 H, s), 4.40-4.58 (2 H, m), 3.60 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.0 min.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]3[CH:20]=[C:21]([CH2:23][O:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=[C:18]3[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:16][CH:15]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C1COCC1>[O:38]1[CH2:39][CH2:40][N:35]([C:17]2[C:18]3[N:19]([CH:20]=[C:21]([CH2:23][O:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:13][CH2:12]3)=[CH:15][N:16]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc2nc(OCc3cn4c(C5CCNCC5)cnc(N5CCOCC5)c4n3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCC(c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)CC1
Temperature: 25 °C

Procedure:
Compound 111 (50 mg, 0.06 mmol, Example 26), DIEA (53 μL, 0.38 mmol) and tert-butyl bromoacetate (12 μL, 0.07 mmol) in THF (1 mL) was heated at 120° C. in a microwave for 10 min. The reaction mixture was allowed to cool to rt and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOAc/hexanes) to obtain compound 27a. Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H38N6O4: 559.3 (M+H). Found 559.3.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.O>CN(C=O)C.[Pd].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>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2cscn2)cc1
Temperature: 120 °C
Yield: 364.4 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.043 mmol) in 5 ml of anhydrous DMF was added 4-tributylstannyl thiazole (0.16 g, 0.43 mmol) and degassed the reaction mixture for 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.05 g, 0.043 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as white solid (0.072 g, 36%). 1H NMR (DMSO-d6, 400 MHz): δ 3.80 (s, 3H), 5.56 (s, 2H), 7.01 (d, J=8.80 Hz, 2H), 7.13 (m, 1H), 7.41-7.50 (m, 4H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 9.18 (s, 1H). MS ES+ (460.32), HPLC (method II) Rt=16.37 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[C@@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:10].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.[C:45]([O-:48])([O-])=[O:46].[K+].[K+]>O1CCOCC1.O>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[O:10])[C@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.[C:45]([OH:48])([C:26]([F:29])([F:28])[F:27])=[O:46]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: O=C(O)C(F)(F)F
Temperature: 100 °C

Procedure:
The mixture of rac-cis-(2-bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone (0.045 g, 0.097 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.024 g, 0.116 mmol), P(PPh3)4 (0.017 g, 0.015 mmol), K2CO3 (0.4 g, 0.291 mmol) and dioxane/H2O (4:1, 3 mL) was degassed for 5 min and heated overnight at 100° C. oil bath. The completion of reaction was monitored by analytical HPLC. The mixture was cooled and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo to obtain a crude residue, which was purified by preparative-HPLC to obtain the title compound as TFA salt. ESI-MS (m/z): 472, [M+1]+.
Reaction SMILES: Cl[CH:2]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])=[CH:47][CH:46]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:5][CH:4]=1.CN(C=O)C.[N-:92]=[N+:93]=[N-:94].[Na+]>C(Cl)(Cl)Cl>[N:92]([CH:2]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])=[CH:47][CH:46]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:5][CH:4]=1)=[N+:93]=[N-:94]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(Cl)c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N=[N+]=[N-])c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
To chloro-bis[4-(12-docosoxydodecyloxy)phenyl]methane (80.9 mg, 66.3 μmol) were added DMF (3 ml), chloroform (1 ml) and sodium azide (40 mg, 621 μmol) and the mixture was stirred at 80° C. for 6 hr. Sodium azide (40.4 mg, 621 μmol) was added, and the mixture was stirred at 90° C. for 1.5 hr. The mixture was cooled to room temperature. Chloroform (2 ml) was added, and the mixture was washed with purified water (3 ml)×3 for partitioning, and the organic layer was evaporated under reduced pressure. The residue was crystallized from acetonitrile to give azido-bis[4-(12-docosoxydodecyloxy)phenyl]methane (72.0 mg, 58.7 μmol, 89%).