Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7]([CH2:9][OH:10])=[N:8][C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7]([CH:9]=[O:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cn1c(CO)nc2cc(Cl)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1c(C=O)nc2cc(Cl)ccc21
Reaction time: 15 h
Yield: 66.7 %

Procedure:
A solution of (5-chloro-1-methyl-1H-benzimidazol-2-yl)methanol (1.5 g, 7.7 mmol) dissolved in CH2Cl2 at room temperature was treated with Dess-Martin periodinane (4.9 g, 11.5 mmol). The reaction was stirred for 15 hours before the solvent was removed. The residue was purified by flash column chromatography (0–3% MeOH in CH2Cl2) to give the product (1.0 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ: 4.16 (s, 3 H), 7.40–7.47 (m, 2 H), 7.90–7.93 (m, 1 H), 10.11 (s, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>O1CCOCC1.C(O)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: BrCCOc1ccccc1-c1nc(-c2ccccc2)no1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CN1CCN(CCOc2ccccc2-c2nc(-c3ccccc3)no2)CC1

Procedure:
1.72 g of 5-[2-(2-bromoethyl)oxy-phenyl]-3-phenyl-1,2,4-oxadiazole are dissolved in 50 ml of anhydrous dioxane and mixed with 2 g of N-methylpiperazine. The solution is refluxed for one hour and then concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with dichloromethane/methanol (90/10). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 1.7 g (78% of theory). m.p.: 251-253° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1.[NH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([NH:23][C:20]([C:18]2[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=2)=[O:22])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)on1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN2CCOCC2)on1
Yield: 68.6 %

Procedure:
As described for example 12b, 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (65 mg, 0.22 mmol) was converted, using 4-amino-morpholine (29 mg, 0.28 mmol) instead of N-aminopyrrolidine HCl, to the title compound (58 mg, 70%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=385.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1Br.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ncsc1Br
Product: Cc1ncsc1-c1ccc(F)cc1

Procedure:
Prepared from the bromothiazole from Step 1 and 4-fluorobenzeneboronic acid by the method described for Example 36 Step 3.
Reaction SMILES: C(OC(=O)C(N)[C@@H](C(OC(C)(C)C)=O)C(N[C@@H](CC1C=CC=CC=1)COC)=O)C1C=CC=CC=1.[C:35]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]([CH2:46][C:47]([OH:49])=O)=[CH:44][CH:45]=2)=[CH:37][CH:36]=1.FC(F)(F)C(O)=O.[CH3:63][NH:64][C:65](=[O:72])[C@H:66]([C:68]([CH3:71])([CH3:70])[CH3:69])[NH2:67].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CO.C(Cl)Cl>[CH3:69][C:68]([CH3:71])([CH3:70])[C@H:66]([NH:67][C:47](=[O:49])[CH2:46][C:43]1[O:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:40][CH:39]=2)=[CH:45][CH:44]=1)[C:65](=[O:72])[NH:64][CH3:63]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC[C@H](Cc1ccccc1)NC(=O)[C@H](C(=O)OC(C)(C)C)C(N)C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 58 %

Procedure:
According to the procedure described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxy-ethyl)-3(R)-t-butoxycarbonyl-amino-succinamic acid benzyl ester, 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid was coupled to L-t-leucine N-methylamide trifluoroacetic acid salt with BOP. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant provided in 58% yield N-[2,2-dimethyl-1(S)-(N-methyl-carbamoyl)-propyl]-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide as an orange foam, which decomposed >75° C. and was used without further purification. 1H NMR (acetone-d6): δ 7.72 (d, 2H, J=8.5 Hz), 7.61 (d, 4H, J=7.7 Hz), 7.45 (t, 2H, J=7.5 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.65 (d, 1H, J=3.3 Hz), 6.56 (d, 1H, J=9.2 Hz), 6.36 (d, 1H, J=3.3 Hz), 5.93 (bs, 1H), 4.22 (d, 1H, J=9.2 Hz), 3.71 (s, 2H), 2.79 (d, 3H, J=4.5 Hz), 0.94 (s, 9H). Anal. Calculated for C25H28N2O3•0.6 H2O•0.1 MTBE: C, 72.21; H, 7.23; N, 6.61. Found: C, 72.10; H, 6.97; N, 6.39.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([OH:16])[CH:10]=1)([O:7][CH3:8])[CH2:5][CH3:6].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([F:29])=[CH:24][CH:25]=2)[CH:20]=1>>[CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]([F:29])=[CH:24][CH:25]=3)[CH:20]=2)[CH:10]=1)([O:7][CH3:8])[CH2:5][CH3:6]
Reactant: CCC(COC)(OC)c1cc(O)cc(F)c1
Reactant: Fc1ccc2ccc(CBr)cc2c1
Product: CCC(COC)(OC)c1cc(F)cc(OCc2ccc3ccc(F)cc3c2)c1
Yield: 76 %

Procedure:
Using the procedure described in Example 12, 2-(5-fluoro-3-hydroxyphenyl)-2-methoxybut-1-yl methyl ether was reacted with 2-bromomethyl-7-fluoronaphthalene to give 2-[5-fluoro-3-(7-fluoronaphth2-ylmethoxy)phenyl]-2-methoxybut-1-yl methyl ether in 76% yield, as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4](Cl)[CH:3]=1.[C:14]1([C@H:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4]([NH:25][C:23]([NH:22][C@@H:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:21])=[O:24])[CH:3]=1
Reactant: COCc1nc(Cl)cc(Cl)c1C#N
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
A mixture of 4,6-dichloro-2-(methoxymethyl)nicotinonitrile (75.7 mg, 0.349 mmol), (R)-1-(1-phenylethyl)urea (77 mg, 0.469 mmol) and Xantphos G2 (39 mg, 0.044 mmol) in THF (2 ml) was sealed, sparged with argon, charged with triethylamine (0.17 ml, 1.220 mmol) and heated to 50° C. for 17 hr. The mixture was cooled and filtered through celite, eluted with EtOAc before it was concentrated in vacuo and purified via flash chromatography (25-100% Et2O/hexane) to provide (R)-1-(4-chloro-5-cyano-6-(methoxymethyl)pyridin-2-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C17H18ClN4O2 [M+H]+ 345. found 345.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[NH2:14][NH2:15].O>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:14][NH:15]2
Reactant: NN
Reactant: CC(C)C(=O)c1c(F)cccc1Br
Solvent: O
Solvent: OCCO
Product: CC(C)c1n[nH]c2cccc(Br)c12
Temperature: 160 °C

Procedure:
A mixture of 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one (1.1 g, 4.5 mmol) and anhydrous hydrazine (0.17 mL, 5.4 mmol) in ethylene glycol (10 mL) is heated for 16 hours at 160° C. Water is added and the mixture is extracted with CH2Cl2. The combined extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography to yield 4-bromo-3-isopropyl-1H-indazole. 1H NMR (CDCl3) 10.1 (br s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 3.99 (m, 1H), 1.43 (d, 6H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:19][CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At RT, 12.6 ml (90.3 mmol) of triethylamine and a solution of 13.77 g (72.2 mmol) of toluene-4-sulphonyl chloride in 200 ml of dichloromethane are successively added dropwise with stirring to a solution of 10.0 g (60.2 mmol) of 4-(2-hydroxyethoxy)benzaldehyde in 300 ml of dichloromethane. The reaction mixture is stirred at RT for 12 h. After addition of 0.15 g (1.2 mmol) of 4-N,N-dimethylaminopyridine, the mixture is stirred at RT for another 4 h. 250 ml of saturated aqueous sodium bicarbonate solution are then added, and the mixture is extracted three times with in each case 100 ml of dichloromethane. The combined organic phases are dried over sodium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→ethyl acetate).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21].C(O)(C)C>CC(C)=O>[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH2:19][C:20]([OH:3])=[O:21]
Reactant: CC(C)=O
Reactant: OCCCOc1ccc(Cl)cc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)CCOc1ccc(Cl)cc1Cl
Yield: 91.5 %

Procedure:
Jones reagent (2.3M, 0.283L, 0.650 mol, CrO3 /H2SO4) is added to a solution of 3-(2,4-dichlorophenoxy)-1-propanol (71.87 g, 0.325 mol) in acetone while maintaining the temperature of the reaction mixture below 40° C. After the addition is complete, isopropanol is added and the reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a blue-green solid which is partitioned between ether and water. The organic phase is separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain the title product as a yellow solid (69.87 g, mp 93°-95° C.).
Reaction SMILES: [CH2:1]1[C:4]2(OCC[O:5]2)[CH2:3][CH:2]1[N:9]1[CH:13]=[C:12]([I:14])[CH:11]=[N:10]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCOCC1.O>[I:14][C:12]1[CH:11]=[N:10][N:9]([CH:2]2[CH2:1][C:4](=[O:5])[CH2:3]2)[CH:13]=1
Reactant: Ic1cnn(C2CC3(C2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(n2cc(I)cn2)C1
Yield: 85.5 %

Procedure:
A solution of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole (Compound 100E, 8.8 g, 29 mmol) and pyridinium p-toluenesulfonate (21 g, 87 mmol) in dioxane-water (140 mL of 1:1 mixture) was stirred at 85° C. for 12 h. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL), the organic layer was washed with water (2×50 mL), dried (Na2SO4) and concentrated to give 6.5 g (yield: 86%) of 3-(4-iodo-1H-pyrazol-1-yl)cyclobutanone. 1H NMR (CDCl3, 300 MHz): δ=3.53-3.57 (m, 2H), 3.73-3.77 (m, 2H), 5.0-5.02 (m, 1H), 7.56 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>C1COCC1>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:24])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (1.13 g, 6.31 mmol) and Et3 N (965 ml, 6.92 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (953 ml, 6.31 mmol) and the reaction mixture was stirred at room temperature for 2 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%) as white needles. mp 137–139° C.; 1H-NMR (CDCl3) δ 1.25–1.29 (m, 3 H), 3.59 (s, 2 H), 4.15–4.20 (m, 2 H), 7.05 (br s, 1 H), 7.13–7.23 (m, 6 H), 7.47–7.51 (m, 1 H), 7.54–7.56 (m, 1 H), 8.01–8.03 (m, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.[F:9][C:10]([F:15])([F:14])[C@@H:11]1[CH2:13][O:12]1>C(#N)C>[O:7]=[S:4]1(=[O:8])[CH2:5][CH2:6][N:1]([CH2:13][C@H:11]([OH:12])[C:10]([F:15])([F:14])[F:9])[CH2:2][CH2:3]1
Reactant: O=S1(=O)CCNCC1
Reactant: FC(F)(F)[C@@H]1CO1
Solvent: CC#N
Product: O=S1(=O)CCN(C[C@H](O)C(F)(F)F)CC1
Yield: 32.8 %

Procedure:
In a 2 ml vial, thiomorpholine 1,1-dioxide (200 mg, 1.48 mmol) was combined with acetonitrile (5.33 ml) to give a colorless solution. (S)-2-(trifluoromethyl)oxirane (332 mg, 257 μl, 2.96 mmol) was added and the resultant mixture was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo to afford 120 mg of (S)-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-1,1,1-trifluoro-propan-2-ol as an oil, which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[NH:50][CH2:49][CH2:48]2>CN(C)C=O>[Br:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:49][CH2:48]2
Reactant: O=C(O)Cc1ccccc1
Reactant: Brc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
To a mixture of phenylacetic acid (0.687 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added Hunig's base (0.882 mL, 5.05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-bromo-2,3-dihydro-1H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was poured onto water, and the resulting precipitate was filtered and air dried to afford the 5-bromo-1-(phenylacetyl)-2,3-dihydro-1 H-indole (1.24 g) as a tan solid.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][C:32]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:31][CH:30]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(-c4ccccc4)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-phenylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.00 mg, 41.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.40-7.30 (m, 8H), 7.30-7.25 (m, 4H), 6.97 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.7 Hz), 5.34 (apparent dd, 1H, J=4.4, 8.0 Hz), 3.40 (m, 2H), 2.98 (m, 2H), 2.53 (apparent sept, partially hidden, 1H, J=8.1 Hz), 2.44 (m, 1H), 2.30-2.10 (m, 6H), 1.93 (d, 2H), 1.26 (d, 6H, J=6.9 Hz); ESMS m/e: 533.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)cc1Cl

Procedure:
To a solution of 2-chloro-1-methoxy-4-methylbenzene (300 mg, 1.92 mmol) in carbon tetrachloride (10.0 mL) was added N-bromosuccinimide (445 mg, 2.50 mmol) and benzoylperoxide (4.6 mg, 0.0192 mmol) and the reaction heated to reflux for 4.5 hours.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[NH:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)C.[OH-].[Na+]>C(O)C.O>[C:21]1([C:12]2[N:11]=[C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[NH:14][C:13]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 55 %

Procedure:
Part B. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid ethyl ester (7.6 g, 0.02 mol) in ethanol (200 mL), was added dropwise a solution of sodium hydroxide (7.6 g) in water (200 mL), and the reaction mixture was stirred at reflux under nitrogen for 3 hours. The reaction mixture was concentrated to half the original volume and then extracted with ether. The ether extracts were discarded. The reaction mixture was acidified to pH 1 with 1N hydrochloric acid and extracted with ether, and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (3.88 g, 0.011 mol) as a white solid, mp 190°-195°. 1H NMR (DMSO-d6) δ12.6(s,1H), 7.6-7.1(m,10H), 3.3-3.1(m,2H), 2.3-2.1(m,3H), 1.8-1.6(m,4H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:15][CH:16]=1)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:15][CH:16]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cn2)cc1
Reactant: NCCc1cccs1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cn2)cc1
Yield: 28.7 %

Procedure:
Using a method similar to Example 455, step 3, using 2-thiophen-2-yl-ethylamine (0.027 mL, 0.227 mmol) and 4-(5-formyl-pyridin-2-yloxy)-benzamide (58 mg, 0.239 mmol) from step 1 (above) gives the title compound (23 mg, 27%). Mass spectrum (ion spray): m/z=353.9 (M+1); 1H NMR (DMSO-d6): 8.08 (d, J=2.1 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.82 (dd, J=2.3 Hz, 8.3 Hz, 1H), 7.31 (bs, 1H), 7.27 (dd, J=1.0 Hz, 5.2 Hz, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.90 (dd, J=3.5 Hz, 5.2 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 3.68 (S, 2H), 2.91 (t, J=7.1 Hz, 2H), 2.72 (t, J=7.1 Hz, 2H), 2.25 (bs, N—H).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.C([O:36][C:37](=[O:41])[CH:38](Br)[CH3:39])C>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([S:16][CH:38]([CH3:39])[C:37]([OH:36])=[O:41])=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)Br
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(Sc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and ethyl-2-bromopropionate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:42]3[CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40][CH2:41]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: FC1(F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 13.9 %

Procedure:
A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.500 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.409 g, 1.5 eq.), 4,4-difluoropiperidine hydrochloride (0.269 g, 1.2), DIPEA (0.220 g, 1.2 eq) and HOBT (0.261 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry. The aqueous layer was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.60 g of crude compound. Purification by preparative TLC (eluting with MeOH/CH2Cl2) afforded 0.090 g compound which was further triturated using ether: petroleum ether to remove aliphatic impurity affording 0.06 g pure compound. Yield: 9.28%.