Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: COC(=O)c1ccnc2cc(-c3ccc(O)cc3)ccc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Yield: 55.9 %

Procedure:
A solution of 90 mg (0.32 mmol) of methyl 7-(4-hydroxyphenyl)-4-quinolinecarboxylate, 196 mg (0.64 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 178 mg (1.29 mmol) of K2CO3 in 2.5 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 98 mg (56%) of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-quinolinecarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J=4 Hz, 1H), 8.81 (d, J=9 Hz, 1H), 8.29 (s, 1H), 7.88-7.85 (m, 2H), 7.64 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.32 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.79 (s, 2H), 4.05 (s, 3H), 3.34 (septet, J=7 Hz, 1H), 1.43 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][CH:16]([CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1)[CH2:17][NH2:18]>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:18][CH2:17][CH:16]([CH3:15])[CH2:19][CH:20]2[CH2:21][CH2:22][CH:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Reactant: CC(CN)CC1CCC(C(C)(C)C)CC1
Product: CCOC(=O)c1c(NCC(C)CC2CCC(C(C)(C)C)CC2)cc(C)nc1C

Procedure:
was synthesized analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 2-methyl-3-(4-tert-butylcyclohexyl)propylamine nD23 :1.4738.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=1
Reactant: Cc1ccc2c(c1)nc([C@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc([C@H](C)N)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of [(S)-1-(5-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (912 mg, 2.59 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM (40 mL) and washed with a saturated solution of NaHCO3 (50 mL). The two phase system was stirred for 10 min, then the organic layer was dried (Na2SO4) and concentrated in vacuo affording (S)-1-(5-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (617 mg, 95%). LCMS: RT 2.10 and 2.23 min [M−NH2] 252.0.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.CCCCC/C=C\C/C=C\CCCCCCCC(O)=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)O

Procedure:
from about 40 to about 70% stearic acid; from about 20 to about 50% oleic and elaidic (C18:3) acids; less than about 12% linoleic (C18:3) acid; and less than about 0.6% linolenic (C18:3) acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[O:30][N:29]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: NCc1noc(C(F)(F)F)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(NCc1noc(C(F)(F)F)n1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and C-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-methylamine hydrochloride (example AI), LC-MS (UV peak area/ESI) 93%, 479.035 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[C:12]([F:13])([F:15])[F:14]
Reactant: COC(=O)c1ccc(CO)cc1C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a solution of 4-hydroxymethyl-2-trifluoromethyl-benzoic acid methyl ester (Example I9) (7.15 g) in dichloromethane (150 ml) was added manganese dioxide (25.1 g). The reaction mixture stirred at ambient temperature for 2.5 hours. The reaction mixture was filtered over a plug of silica gel and the filtrate concentrated to give 4-formyl-2-trifluoromethyl-benzoic acid methyl ester (5.98 g), which was used without further purification. 1H-NMR (CDCl3, 400 MHz): 10.11 (s, 1H), 8.25-7.59 (m, 3H), 3.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][C@H:24]3[CH2:25][CH2:26][CH2:27][O:23]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCC1CCCO1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C[C@H]1CCCO1

Procedure:
Compound IIj was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and R)-(tetrahydrofuran-2-yl)methanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[C:14]2=[O:17])=[CH:9][CH:8]=1.[CH3:22]O>>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC(=O)O)CC2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1CCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under cooling, 1.8 ml of thionyl chloride was dropwise added slowly to 20 ml of methanol. After 10 minutes, 1.5 g of 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.6 g of methyl 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([C:11]([F:10])([F:19])[F:20])[CH:13]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: Cc1ccc(C)c(Nc2cccc(C(F)(F)F)c2)c1
Temperature: 110 °C
Yield: 93.5 %

Procedure:
Following general procedure E, a mixture of 2-chloro-p-xylene (134 μL, 1.0 mmol), 3-(trifluoromethyl)aniline (150 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a clear oil (248 mg, 94%). 1H NMR (300 MHz, CDCl3) δ: 7.38 (t, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.16 (m, 3H), 7.08 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 5.53 (s, 1H), 2.39 (s, 3H), 2.28 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 145.5, 139.8, 137.1, 132.6, 132.2, 131.8, 131.8, 131.4, 130.1, 130.0, 127.5, 126.4, 124.9, 124.9, 124.8, 122.8, 122.1, 122.0, 119.2, 119.1, 116.3, 116.3, 112.8, 21.4, 17.7 ppm. IR (neat, cm−1): 3391, 3021, 2924, 1613, 1485, 1337, 1165, 1124, 787, 699. Anal. Calcd. for C15H14F3N: C, 67.91; H, 5.32. Found: C, 68.02; H, 5.31.
Reaction SMILES: Cl[C:2]1[C:3](C#N)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].ClC1C=CC(S([C:38]2C3C(=CC=CC=3NS(C)(=O)=O)[N:40](CC(O)=O)[C:39]=2C)(=O)=O)=CC=1.ClC1C=CC(SC2C3C(=CC=C(C)C=3)NC=2C)=CC=1>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[CH:2][C:3]=3[NH:40][CH2:39][CH3:38])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH3:15])(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2c(C#N)c(Cl)ccc2n1CC(=O)O
Reactant: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)O
Agent: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Product: CCNc1cccc2c1c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of example 2 part (d) using the by product from example 22 part (a). Product was purified using reverse phase preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:19]=[C:18]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[CH:16][N:15]=1>>[Br:13][C:14]1[CH:19]=[C:18]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:16][N:15]=1
Reactant: CON(C)C(=O)C=Cc1ccnc(Br)c1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccnc(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 42.4 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (73.8 mL, 62.0 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (41.3 mL, 62.0 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then 3-(2-bromo-pyridin-4-yl)-N-methoxy-N-methyl-acrylamide (5.6 g, 20.7 mmol, in diethyl ether/tetrahydrofuran 30.0 mL/30.0 mL) prepared in Step 2 was added thereto at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, quenched with distilled water at room temperature, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 2.9 g of the titled compound as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([NH:26][CH3:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].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>C(Cl)Cl.CCOC(C)=O>[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42]([N:26]([CH3:27])[C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)=[O:44])=[O:38])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CN[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl(7R)-14-cyclohexyl-7-(methylamino)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 5) and N-(tert-butoxycarbonyl)-β-alanine (1.2 eq) in DCM (0.15 M) was treated with HATU (1.3 eq.) and DIPEA (3 eq.) and the resulting mixture was stirred for 90 min at RT. The reaction was diluted with EtOAc and the combined organic layers were washed with 1N HCl (aq), sat aq NaHCO3 then brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 590 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=O)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[N:12][CH2:11][CH2:10]2
Reactant: COc1ccc(CCNC(=O)CCc2ccc(Cl)cc2)cc1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1C)CCN=C2CCc1ccc(Cl)cc1
Yield: 52.3 %

Procedure:
Heat a mixture of the amide from step A (10.0 g), phosphorous pentoxide (25 g), phosphorous oxychloride (15 mL) and xylene (250 mL) at reflux for 2 h. Cool the reaction mixture, slowly add water (500 mL), basify using NaOH and extract with benzene. Concentrate the benzene extract to a residue and triturate with diethyl ether to give 6-methyl-7-methoxy-1-[2-(4-chlorophenyl)ethyl]-3,4-dihydroisoquinoline (4.95 g), mp=122°-124° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:43])[CH:22]([NH:30][C:31]([C:33]2[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([Cl:42])=[CH:37][CH:36]=3)=[O:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[CH2:23]([CH:22]([NH:30][C:31]([C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][C:38]([Cl:42])=[CH:37][CH:36]=2)=[O:32])[C:21](=[O:43])[N:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCNCC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.3 h

Procedure:
Trifluoroacetic acid (4 ml) was added to 4-{2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionyl}-piperazine-1-carboxylic acid tert-butyl ester (0.6 mmol) at 0° C. and the resulting solution was stirred for 0.3 hours and concentrated. The residue was partitioned between ethyl acetate and 2N NaOH, the organic layer separated and washed with brine, dried over Na2SO4, concentrated and the resulting solid triturated with ether: Yield 189 mg, 77%; HPLC (60/40) 2.63 minutes (99%);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C)C=O.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichloromethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted with water and extracted into ethyl acetate and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:17])[CH3:20]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 56.8 %

Procedure:
10.0 g (51.8 millimoles) of 3-(p-aminobenzoyl)propionic acid, 6.7 g (61.7 millimoles) of ethyl chloroformate and 100 ml of absolute tetrahydrofuran are refluxed for 10 hours. The product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 7.8 g (57% of theory) of 3-(p-ethoxycarbonylaminobenzoyl)-propionic acid are obtained as pale beige crystals, of melting point 206°-207° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[C:20]([CH3:25])[CH:19]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(F)ccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 80.2 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 4-fluoro-2-methylphenol (20 μL, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(4-fluoro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 80%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.92 (d, J=8.2 Hz, 2H), 7.54-7.63 (m, 3H), 6.91-7.08 (m, 3H), 5.16 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6](F)[N:5]=1)[CH3:2].C(N(CC)CC)C.O.[NH2:20][NH2:21].NN>O.C(#N)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([NH:20][NH2:21])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(F)cc(F)n1
Reactant: NN
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1nc(F)cc(NN)n1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
A mixture of 100 g of 94 percent purity (0.59 mol) 2-ethoxy-4,6-difluoropyrimidine, 275 mL of acetonitrile, and 107 g of water was prepared and cooled to 10° C. To this was added 68 g (0.67 mol) of triethylamine and then 34 g (0.68 mol) of hydrazine hydrate, slowly with stirring and cooling (at 5° to 10° C). When all of the hydrazine had been added, the mixture was stirred another 15 min with cooling and was then allowed to warm. After a total of 1 hour, the solids that formed were recovered by vacuum filtration and were washed twice with 100 mL portions of water and then with 50 mL of ethanol. The title compound, which was obtained as a white solid melting at 141°-143° C., amounted to 79.7 g (80 percent of theory).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:17](#[N:19])[CH3:18]>>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][C:17]#[N:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: N#CC=C(c1ccccc1)c1ccccc1
Yield: 73.3 %

Procedure:
To a solution of benzophenone (9.1 g, 50 mmol) in acetonitrile (20 mL) was added potassium hydroxide (3.3 g, 50 mmol) in acetonitrile (25 mL). The solution was refluxed for 8 hours. The hot reaction mixture was poured into 100 g crushed ice and then extracted with dichloromethane. The organic extract was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography (diethyl ether/hexanes) to give 3,3-diphenylacrylonitrile (7.7 g, 73.3%) as an oil.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Cl-].[CH:11]1[C:16](N=C=S)=[CH:15][C:14]2[C:20]([O:22][C:23]3([C:33]4[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:32]=4[O:31][C:25]4[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:24]3=4)[C:13]=2[CH:12]=1)=[O:21]>CS(C)=O>[CH:11]1[CH:16]=[CH:15][C:14]([C:20]([OH:22])=[O:21])=[C:13]([C:23]2[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=3[O:31][C:32]3[C:33]=2[CH:34]=[CH:35][C:36]([CH:37]=3)=[O:38])[CH:12]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
Recombinant purified proteins were labelled with fluorescein-isothiocyanate (FITC, Molecular Probes F143). Reaction was carried out by adding proteins to 10 mM sodium phosphate, 50 mM NaCl buffer pH 7 at a final protein concentration of 1 mg/ml. Labelling reaction was started by adding FITC dissolved in DMSO at a concentration of 20 mg/ml to reach 20:1 molar ratio with respect to the protein concentration. The mixture was left to react at room temperature for an hour. Labelled protein was separated from the free fluorescein on a PD-10™ column (Pharmacia) prior to dialysis in the binding buffer (1 mM sodium phosphate 150 mM NaCl, pH 7.4).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[N:38][CH:39]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@H:25]([C:34]3[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[OH:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: FC(F)(F)c1ccc(Br)cn1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 5-bromo-2-(trifluoromethyl)pyridine.