Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=1[C:9]([OH:11])=[O:10].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O.CN(C=O)C>[CH2:15]([O:10][C:9](=[O:11])[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[O:12][CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(O)c1C(=O)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OCc2ccccc2)c1C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 118.8 %

Procedure:
While stirring a mixture of 6-methoxysalicylic acid (5.07 g, 30.15 mmol) and sodium hydride (60% w/w, 3.02 g, 75.38 mmol) under cooling with ice, DMF (30 mL) was added thereto. The mixture solution was stirred at the same temperature for 10 minutes, and then benzyl bromide (8.95 mL, 75.38 mmol) was added thereto over 5 minutes and the reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 2.5 hours. To the reaction mixture was added a saturated ammonium chloride aqueous solution and water under cooling with ice, and the mixture was extracted with ether. The organic layer was washed with water and a saturated ammonium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10 to 1:5)] to obtain the title compound (6.24 g, 59%).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[CH:13][C:14]([O:16][C@@H:17]2[CH:21]3[O:22][CH2:23][C@@H:24]([O:25]C4CCCCO4)[CH:20]3[O:19][CH2:18]2)=[O:15])=[CH:10][CH:9]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][C@@H:17]2[CH:21]3[O:22][CH2:23][C@@H:24]([OH:25])[CH:20]3[O:19][CH2:18]2)=[O:15])=[CH:32][CH:33]=1
Reactant: O=C(C=Cc1ccc(OC2CCCCO2)cc1)O[C@H]1COC2C1OC[C@H]2OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)O[C@H]1COC2C1OC[C@H]2O
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A mixture of 9.1 g of 3-(R)-(tetrahydropyran-2-yloxy)-hexahydro-furo[3,2-b]furan-6-(S)-yl 4-(tetrahydropyran-2-yloxy)cinnamate (25), 0.48 g of pyridinium 4-toluenesulfonate and 60 ml of absolute ethanol was heated at 60° C. for 3 hours under a nitrogen atmosphere. A clear solution was obtained which was added dropwise to 50 g of ice and 100 g of water with vigorous stirring. A white solid precipitated. It was filtered off, washed with water and dried in a dessicator over silica. 3.7 g of a white powder was obtained (yield: 66%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:11]2[NH:15][CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:37])[NH:32][CH2:33][C:34](O)=[O:35])[CH:27]=[CH:28][CH:29]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:37])[NH:32][CH2:33][C:34]([N:15]2[CH:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:12][CH2:13][CH:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:35])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Yield: 18.3 %

Procedure:
0.9 cm3 of sulphinyl chloride is added slowly to a suspension of 3.1 g of tert-butyl (2RS,5SR)-5-phenylprolinate and 2.6 g of 2-[3-(3-methylphenyl)ureido]acetic acid in 100 cm3 of anhydrous 1,2-dichloroethane heated to reflux. The reaction mixture is then heated under reflux for 15 minutes, then cooled to 50° C. and neutralized to a pH of 7-8 by addition of a 10% aqueous sodium bicarbonate solution. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (98/2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the vicinity of 45° C. After recrystallization in acetonitrile, 1 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate, melting at 156° C., is obtained.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[F:15]C1C=C2C(CC/C/2=C\C(Cl)=O)=CC=1>>[F:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)/[C:8](=[CH:11]/[C:12]([NH2:14])=[O:13])/[CH2:7][CH2:6]2
Reactant: NC(=O)/C=C1\CCc2ccc(F)cc21
Reactant: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Product: NC(=O)/C=C1\CCc2cc(F)ccc21
Yield: 44 %

Procedure:
This compound was prepared in a similar manner to that described for (E)-2-(6-fluoro-1-indanylidene)acetamide Example 1k by substituting (E)-2-(5-fluoro-1-indanylidene)acetyl chloride (3.16 g, 0.015 mol) for (E)-2-(6-fluoro-1-indanylidene)acetyl chloride. Recrystallization from acetonitrile: water mixtures gave 1.28 g (44%) of (E)-2-(5-fluoro-1-indanylidene)acetamide as a white solid; m.p., 191°-193° C.;
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C@@:3]1([NH:8]C(=O)OC(C)(C)C)[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:28]1[C:47]([C:48]2[N:52](C3CCCCO3)[N:51]=[CH:50][CH:49]=2)=[CH:46][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[O:33])=[CH:30][N:29]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(C(F)(F)F)=O>CC(O)C.C(Cl)Cl>[NH2:8][C@:3]1([C:2]([F:1])([F:16])[F:17])[CH2:7][CH2:6][N:5]([C:28]2[C:47]([C:48]3[NH:52][N:51]=[CH:50][CH:49]=3)=[CH:46][C:31]([C:32]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:39][CH:40]=3)=[O:33])=[CH:30][N:29]=2)[CH2:4]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(F)(F)F)CCNC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: N[C@]1(C(F)(F)F)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
(R)-tert-butyl 3-(trifluoromethyl)pyrrolidin-3-ylcarbamate (92 mg, 0.362 mmol) and DIPEA (0.075 mL, 0.428 mmol) were added to a solution of 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1, 100 mg, 0.214 mmol) in iPrOH (1.5 mL) and the RM was stirred at 130° C. overnight. The mixture was filtered and the solvent was evaporated off under reduced pressure to give a residue which was treated with 2 N aqueous citric acid and extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was treated with TFA (3 mL) in DCM (2 mL) and stirred for 4 h at RT. The solvent was evaporated off under reduced pressure and the residue was purified by SFC (Column 4-EP, from 17% to 22% in 6 min) and lyophilized in water/MeCN (min. vol.) to give the title compound as a beige powder. UPLC-MS (Condition 3) tR=1.03 min, m/z=501.1 [M+H]+, m/z=499.2 [M−H]−; 1H NMR (600 MHz, DMSO-d6) δ ppm 1.73-1.84 (m, 1H) 1.94-2.07 (m, 1H) 2.26 (br. s, 2H) 2.95-3.15 (m, 1H) 3.29-3.42 (m, 1H) 3.47-3.60 (m, 2H) 6.43 (br. s, 1H) 7.34 (d, J=8.47 Hz, 2H) 7.80-7.91 (m, 3H) 8.08 (s, 1H) 8.75 (br. s, 1H) 10.24 (s, 1H) 12.98 (br. s, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([F:25])=[CH:18][C:19]=3[F:24])[N:14]=2)[CH:12]=1)=[O:7])C>C1COCC1>[F:24][C:19]1[CH:18]=[C:17]([F:25])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([N:11]1[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1)=[N:14]2
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
Aqueous potassium hydroxide (1 M, 1.7 mL, 1.7 mmol) was added to 1-(5,7-difluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.152 g, 0.475 mmol) in THF (1.7 mL). The reaction mixture was allowed to stir at room temperature for 18 h and was then concentrated. The residue was redissolved in water (5 mL) and brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected by filtration to yield the titled compound (0.137 g, 98% yield). MS (ESI/Cl): mass calcd. for C12H6F2N4O3, 292.0; m/z found, 293.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.07 (s, 2H), 8.93 (d, J=0.4 Hz, 1H), 8.28 (s, 1H), 7.44-7.27 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])\[CH3:8])(=[O:3])[CH3:2].C([O:19]O)(C)(C)C.C(O)(=O)C1C(=CC=CC=1)O>[Al].C1(C)C=CC=CC=1.C(Cl)Cl.O=[Mn]=O>[CH3:8]/[C:7](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:14])/[CH:13]=[O:19])=[CH:6]\[CH2:5][O:4][C:1]([CH3:2])=[O:3]
Reactant: CC(C)(C)OO
Reactant: CC(=O)OC/C=C(\C)CCC=C(C)C
Agent: O=[Mn]=O
Agent: O=C(O)c1ccccc1O
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC/C=C(\C)CC/C=C(\C)C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
Geranyl acetate was oxidized as described previously with some modification (21). Forty milliliters (0.36 mol) of 90% tert-butyl hydroperoxide was added to a stirred suspension of 1.11 g (0.01 mol) of SeO2, 1.4 g (0.01 mol) of salicylic acid, and 75 ml of CH2Cl2 in a 250 ml round bottom flask covered in aluminum foil. The resulting solution was allowed to stir to homogeneity at room temperature before being placed at 0° C. After ten minutes, 21.5 ml (0.10 mol) of geranyl acetate (4) was introduced dropwise. The mixture was stirred for 5 h at 0° C., and then for 20 h at rt. TLC analysis indicated the presence of starting material and two oxidized products (Rf 0.38 aldehyde, Rf 0.19 alcohol). The solution was diluted with 100 ml toluene, and solvents were removed under reduced pressure. The residue was then dissolved in toluene, washed with 5% NaHCO3 to remove H2SeO3, saturated CuSO4, saturated aqueous Na2S2O3 (2×), water, brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure affording a crude oil, which was dissolved in 100 ml dry CH2Cl2 and cooled to 0° C. 40.95 g (0.47 mol) of activated MnO2 was added, and the suspension was stirred for 5 h at 0° C., then overnight at rt. The mixture was filtered over a short bed of Celite, and washed thoroughly with dry CH2Cl2. Solvent was evaporated under reduced pressure to yield a crude, pale yellow oil which was purified by flash chromatography on silica gel (5% EtOAc in hexane) affording 10.68 g (51 %) of 5 as a colorless oil; 1H NMR (C6H6, 200 MHz) δ9.47 (s, 1H), 5.98 (t, 1H, J=6.9 Hz), 5.48 (t, 1H, J=6.9 Hz), 4.75 (d, 2H, J=6.8 Hz), 2.11 (q, 2H, J=7.3 Hz), 1.92 (t, 2H, J=7.3 Hz), 1.91 (s, 3H), 1.79 (s, 6H), 1.59 (s, 3H); 13C NMR (50.3 MHz) δ195.47, 171.39, 153.70, 140.73, 140.08, 120.01, 61.48, 38.13, 27.33, 21.37, 16.77, 9.62.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:20])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:6]=[CH:7][CH:8]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
To a solution of N-(3-aminophenyl)-3-nitrobenzamide hydrochloride (0.200 g, 0.681 mmol) and 2,4,5-trichloropyrimidine (0.071 mL, 0.619 mmol) in DMF (1.6 mL) was added potassium carbonate (0.30 g, 2.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give the desired product as a light brown powder (330 mg). LCMS for C17H11Cl2N5O3 (M+H)+: m/z=403.9, 405.9, 407.9. 1H NMR (400 MHz, CD3OD): δ 8.82 (t, J=2.0 Hz, 1H), 8.45 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.34 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 8.24 (s, 1H), 7.97 (br, 2H), 7.76 (t, J=8.0 Hz, 1H), 7.56 (m, 1H), 7.43 (ddd, J=8.0, 2.0, 1.2, 1H).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5](=[C:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)C.[OH-].[Na+]>C(O)C>[CH:27]1[C:22]2[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[C:17](=[C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=3)[C:4]([OH:32])=[O:3])[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=C1c2ccccc2CCc2ccccc21)c1cccc(NS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(C(C(=O)O)=C2c3ccccc3CCc3ccccc32)c1
Yield: 20 %

Procedure:
Treat (10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-(3-methanesulfonylamino-phenyl)-acetic acid ethyl ester with a 50:50 mixture of 1N NaOH and ethanol and heat under reflux conditions for 14 hours. Acidify with 1N HCl and collect the solid by filtration and dry. Purify by reverse phase HPLC to obtain a 20% yield of the title compound. MS(ES)=437(+NH3)
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH3:9])[CH:7]=[O:8])(=[O:3])[CH3:2].C(OCCCC=O)(=O)C>CO>[C:1]([O:4][CH2:5][CH:6]([CH3:9])[CH2:7][OH:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)C=O
Agent: CC(=O)OCCCC=O
Solvent: CO
Product: CC(=O)OCC(C)CO
Yield: 99 %

Procedure:
The procedure in Example 4 was followed except that 3-acetoxy-2-methylpropionaldehyde was hydrogenated in place of 4-acetoxybutyraldehyde, in the presence of 5% by weight of methanol. After a hydrogenation time of 30 minutes and after working up as described in Example 4, pure 3-acetoxy-2-methylpropan-1-ol was obtained in 99% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CN(C=O)C>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[O:9]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Reaction time: 1.5 h

Procedure:
(N,N,N′,N′-Tetramethyl-o-(1h-benzotriazol-1-yl)uronium tetrafluoroborate (6.95 g, 21.64 mmol) was added to a solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-4-fluorobenzoic acid (5.00 g, 14.43 mmol) and diethylamine (8.00 mL, 77 mmol) in DMF (70 mL) at 0° C. The reaction was stirred 1.5 hours before being quenched with saturated sodium bicarbonate (100 mL). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, 10% aqueous sodium carbonate, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to provide a residue that was purified by silica gel chromatography (1:2 EtOAc in hexane) to provide 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-4-fluorobenzamide. MS m/z=403.0 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][C:19]([C:17]1[S:16][C:14]2[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)[N:11]=[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:13]=2[CH:18]=1)=[O:21]
Reactant: NCCO
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: O=C(NCCO)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to ethanolamine via General Procedure B. The product was purified via reverse phase HPLC to give 10.2 mg of 128. MS (Q1) 425.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[C@H:12]([C:33](O)=[O:34])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][NH:36][C:33]([C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]1[CH2:15][C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:20][C:19]=1[F:31])=[O:34]
Reactant: NCCO
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)NCCO)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
Using general procedure D (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]—1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) was coupled with 2-aminoethanol to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (2-hydroxy-ethyl)-amide. White solid. MS 562.5 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]1[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH2:11]1
Reactant: Cc1ccc(C2CN(C(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2CNC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 126-2 (37 mg, 0.15 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 2 h. The solvent was removed by rotary evaporation, followed by three cycles of dilution with DCM and evaporation to provide 126-3 that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: CC(C)c1ccc(NCc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Following the procedure described in Example 1A, step 1, 4-(trifluoromethoxy)benzaldehyde and 4-isopropylaniline gave the title compound as a colorless oil.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[CH:14]1[C:19]([CH2:20][CH2:21]O)=[CH:18][C:17]([OH:23])=[C:16]([OH:24])[CH:15]=1.C1C(CCO)=CC=C(O)C=1>>[C:1]([O:13][CH2:21][CH2:20][C:19]1[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([OH:23])[CH:18]=1)(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: OCCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: OCCc1ccc(O)cc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccc(O)c(O)c1

Procedure:
The protocol derived from Example 14 above is applied with caffeic acid and 3-hydroxytyrosol instead of caffeic acid and tyrosol; the compound obtained is 2-(3,4-dihydroxyphenylethyl) trans-caffeoate (formula IVb2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16](=[CH2:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:25])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:25][CH2:22]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OCC)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1([C@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 852 mg (2.8 mmol) of ethyl 2-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)acrylate and 5 mg (0.02 mmol) of palladium acetate was added 100 ml of diethyl ether, followed by dropwise addition of a solution of excess (10 equivalents) diazomethane in diethyl ether while ice cooling. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was evaporated and the resulting residue was applied to a silica gel column chromatography to yield 890 mg (quantitative) of the title compound as an oily substance from the eluate of n-hexane:ethyl acetate=3:1.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][C:52]3=[O:57])[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][C:52]3=[O:57])[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: Cl
Product: CCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)biphenyl by cleaving the triphenylmethyl group with methanolic hydrochloric acid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)S(O[C:27]1[CH:32]=[CH:31][C:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)(=O)=O.O>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([C:7](=[N:20][C:27]2[CH:32]=[CH:31][C:30]([C@H:33]3[CH2:34][CH2:35][C@H:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:38]3)=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)CC1
Temperature: 25 °C

Procedure:
Caesium carbonate (4.0 g, 12.4 mmol), R-BINAP (330 mg, 0.53 mmol), palladium acetate (119 mg, 0.53 mmol) and benzophenone imine (2.2 mL, 13.2 mmol) were added sequentially, each in one portion, to a stirred solution of trans-ethyl 2-[4-(4-{[(trifluoromethyl)-sulfonyl]oxy}phenyl)cyclohexyl]propanoate in THF (50 mL) and the reaction mixture was heated at 65° C. for 70 h under an argon atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo to leave a residue. The residue was taken up in EtOAc (75 mL) and H2O (25 mL) was added. The layers were separated and the organic layer was extracted with brine (25 mL), dried and concentrated in vacuo to leave a residue. The residue was purified by chromatography, eluting with 10-50% EtOAc in isohexane, to give the title compound (2.3 g, 59%) as an oil; 1H NMR δ (CDCl3) 1.07-1.25 (2H, m), 1.15 (3H, d), 1.3 (3H, t), 1.35-1.5 (2H, m), 1.55-1.7 (2H, m), 1.72-1.8 (1H, m), 1.83-1.95 (2H, m), 2.24-2.43 (2H, m), 4.15 (2H, q), 6.7 (2H, d), 7.0 (2H, d), 7.15 (2H, d), 7.23-7.35 (1H, m), 7.4 (2H, dd), 7.47-7.55 (2H, m), 7.78 (2H, d), 7.84 (1H, d); MS m/e MH+ 440.