Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:19]=O)=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N+:25](CC)([O-])=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:19]#[N:25])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Temperature: 115 °C
Yield: 44.5 %

Procedure:
To a solution of 1-benzyl-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbaldehyde (45 mg, 0.17 mmol) from step 3 in acetic acid (0.38 mL, 6.6 mmol) was added nitroethane (0.24 mL, 3.4 mmol) and sodium acetate (270 mg, 3.4 mmol). The reaction mixture was heated at a sealed tube at 115° C. overnight. Added some water and extracted it with ether. Combined organic layer and evaporated under vacuum. It was purified by prep TLC eluting with 10% ethyl acetate-hexane and providing 20 mg (45%) of the title compound. 1H-NMR (CDCl3) δ 7.36-7.21 (m, 3H), 7.18-7.14 (m, 2H), 6.99 (s, 1H), 5.98 (s, 1H), 4.48 (s, 2H), 3.41 (t, J=5.7Hz, 2H), 2.70 (t, J=6.4Hz, 2H), 1.97 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:10].BrC1C=CC(C[NH:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])=CC=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])=[CH:4][C:3]=1[Cl:10]
Reactant: COC(CNCc1ccc(Br)cc1)OC
Reactant: O=Cc1ccc(Br)c(Cl)c1
Product: COC(CNCc1ccc(Br)c(Cl)c1)OC

Procedure:
Starting from 4-Bromo-3-chloro-benzaldehyde, the title compound was prepared by the method described for (4-Bromo-benzyl)-(2,2-dimethoxy-ethyl)-amine (1). Rt=0.94 min (Method C). Detected mass: 308.3/310.3 (M+H+).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][CH2:9][C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:15][CH2:14][CH2:13][N:12]([C:16](OC(C)(C)C)=[O:17])[CH2:11]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C(OC(=O)C)(=O)C>ClCCl>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C:10]([CH2:9][OH:8])([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:11]1)(=[O:17])[CH3:2]
Reactant: Cc1ccc(CC2(CO)CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(CO)(Cc2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (12.5 ml) was added to a solution of the product from STEP 3 (0.48 g, 1.4 mmol) in 12.5 ml dichloromethane at 0° C. The reaction was allowed to warm to room temperature. After 2 h, the reaction was concentrated, and dried in vacuo. The residue was dissolved in 20 ml dichloromethane, then triethylamine (1.82 g, 18.0 mmol) and dimethylaminopyridine (30 mg) were added. Acetic anhydride (1.13 ml, 12.0 mmol) was added to the above mixture at 0° C. The reaction mixture was allowed to warm to room temperature. After 18 h, the reaction was diluted with 150 ml dichloromethane, washed with 10 ml H2O, 5 ml brine, dried with MgSO4, and concentrated. The residue was dissolved in 25 ml methanol. An aqueous saturated K2CO3 solution (15 ml) was added at 0° C. The reaction was allowed to warm to room temperature. After 1.5 h, glacial acetic acid was added to adjust PH value to 6.5. The reaction was concentrated and product was extracted with ethyl acetate. The organic extracts were washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH=90/10/0.2) to afford 0.14 g of an viscous oil. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[Cl:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:53][CH2:52][C:51]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=2[Cl:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: NCc1ccc(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCc1ccc(F)cc1Cl)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and 2-chloro-4-fluorobenzylamine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C22H15BrClFN4O3S, 548.0; m/z found, 549/550 [M+H]+, 571/573 [M+Na]+. HPLC (reverse phase): RT=9.86 min. 1H NMR (500 MHz, CDCl3): 11.29 (s, 1H), 8.88 (dd, J=15.3, 6.0 Hz, 2H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.32 (dd, J=8.4, 1.8 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.4, 7.4 Hz, 1H), 7.43 (dd, J=8.5, 6.0 Hz, 1H), 7.16 (dd, J=8.3, 2.6, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.5, 2.1 Hz, 1H), 7.01 (ddd, J=8.2, 8.2, 2.5 Hz, 1H), 6.38-6.33 (m, 1H), 4.57 (d, J=6.0 Hz, 1H).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[ClH:19].C(O)(=O)C.N([O-])=O.[Na+]>O.C(Cl)(Cl)Cl>[Cl:19][C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cl
Reactant: CCOC(=O)c1sc(N)nc1-c1ccc(F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(Cl)nc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.0441 mole) of ethyl 2-chloro-(p-fluoro)benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C. To 4.0 g (0.015 mole) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate was added 30 ml. of concentrated hydrochloric acid and 30 ml. of glacial acetic acid. The carboxylate did not dissolve completely. To this mixture was added 30 ml. of chloroform. The carboxylate dissolved gradually into the chloroform solution. the reaction mixture was cooled to 0°-5° C. with an ice bath. To the above mixture was added with vigorous stirring 4.0 g (0.058 mole) of sodium nitrite. The reaction mixture was stirred at 5°-10° C. for 30 minutes and poured into a solution of 1.48 g (0.0150 mole) of cuprous chloride in 20 ml. of concentrated hydrochloric acid. After the gas evolution subsided, the reaction mixture was diluted with water. The chloroform layer was separated and the aqueous layer was extracted with chloroform. The combined chloroform solution was washed with water followed by saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residual solid was recrystallized from ethanol to give 3.3 g (77%) of ethyl 2-chloro-4-(p-fluorophenyl)-5-thiazolecarboxylate as orange needles, m.p. 113°-114° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)=[CH:5][C:4]=2[N:3]=1.C(O)C>[Pt].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3cc(OCc4cccc([N+](=O)[O-])c4)ccc3c2n1CC(C)(C)O
Agent: [Pt]
Solvent: CCO
Solvent: CO
Product: COCCc1nc2c(N)nc3cc(OCc4cccc(N)c4)ccc3c2n1CC(C)(C)O
Reaction time: 5 h
Yield: 53.4 %

Procedure:
1-[4-Amino-2-(2-methoxyethyl)-7-(3-nitrobenzyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (3.1 g, 6.66 mmol) was mixed with 100 mL of warm ethanol and 1 g of 5% platinum on carbon. The mixture was shaken under hydrogen pressure (50 psi, 3.4×105 pa) for 5 hours. The material had come out of solution so an additional 100 mL of methanol and 0.5 g platinum catalyst were added. After shaking under hydrogen pressure overnight, the mixture was filtered through CELITE filter agent. The filter cake was washed with 3×75 mL portions of hot methanol and the filtrates were combined and concentrated under reduced pressure. An orange foam resulted which was purified by column chromatography using silica gel. The polar component of the eluent was chloroform:methanol: 2% aqueous ammonium hydroxide 80:18:2 (CMA), and elution was carried out with CMA:chloroform in a gradient from 0:100 to 40:60. Fractions containing product were combined and concentrated to yield 1.55 g of 1-[4-amino-7-(3-aminobenzyloxy)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid. A small portion was recrystallized from acetonitrile to provide an analytical sample, mp 203.0-206.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=O.Cl.[NH2:19][OH:20].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:19][OH:20]
Reactant: NO
Reactant: Cc1ccccc1-n1ccc(Cl)c(C=O)c1=O
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccccc1-n1ccc(Cl)c(C=NO)c1=O
Temperature: 100 °C
Yield: 94.6 %

Procedure:
A mixture of 4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step B (6.00 g), hydroxylamine hydrochloride (2.53 g), conc. hydrochloric acid (0.0740 mL) and 2-propanol (60 mL) was heated at 100° C. for 2 hr, and the mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.02 g).
Reaction SMILES: [CH3:1][C@H:2]([NH:10][CH3:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-:13].[Na+].[Na+].C(=O)(O)[O-]>>[CH3:1][C@H:2]([NH:10][CH3:11])[C@@H:3]([OH:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CN[C@@H](C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN[C@@H](C)[C@@H](O)c1ccccc1
Reaction time: 0.5 h

Procedure:
96-well microtitre plates were coated overnight at room temperature with monoclonal anti-methamphetamine antibody (East Coast Biologicals, USA) at 5 :g/ml, 100 :l/well, in 50 mM sodium carbonate/bicarbonate buffer, pH 9.6. The plate was washed 3 times with wash buffer and blocked in the same buffer for 30 minutes. 3-fold dilutions in assay buffer of the enzyme-drug conjugate (100 :l/well) were added. After 30 minutes incubation at room temperature, the plate was washed 3 times and the substrate solution added as described before. FIG. 4 shows the titration profile obtained with this conjugate. The conjugate retained both enzyme activity and the ability to bind to immobilised anti-methamphetamine antibody allowing its use in drug capture competitive enzyme immunoassay.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.O>O1CCCC1>[F:28][CH:27]([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:8]2[C:7](=[O:33])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:16][C:17]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:19])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N2CCOCC2)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (400 mg, 0.86 mmol) in tetrahydrofurane was added carbonyldiimidazole (160 mg, 1 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.12 ml, 1.3 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile: water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (200 mg, 44%): mp, 109-111° C.; 1HNMR (CDCl3): 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.02 (dd, J=5, 17.5 Hz, 1H, CHHCO), 3.49-3.68 (m, 8H, morpholine ring), 3.9 (dd, J=7.5, 17.5 Hz, 1H, CHHCO), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 5.84 (dd, J=5, 10 Hz, 1H, CHN), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.11-7.16 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.75 (d, J=7.5 Hz, 1H, Ar), 9.50 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 35.1, 42.7, 46.6, 51.9, 65.5, 67.2, 67.5, 112.6, 114.4, 115.9, 116.7, 118.6, 120.8, 120.9, 123.5, 125.5, 131.9, 136.6, 138.2, 138.5, 140.6, 151.3, 168.6, 168.7, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O7: C, 58.75; H, 5.12; N, 7.91. Found: C, 58.48; H, 5.09; N, 7.79;
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][S:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:5]4[CH:4]=[C:3]([CH2:1][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[S:7][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)[CH2:21][CH2:22]1)(=[O:27])=[O:28]
Reactant: C1CCNC1
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.9 %

Procedure:
To 5-(5-formyl-3-thienyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.08 mmol) in a mixture of dichloromethane (1.25 mL) and methanol (0.5 mL), pyrrolidine (0.07 mL, 0.8 mmol) and 2 drops of acetic acid were added. After the reaction mixture was stirred at room temperature for 6 hours, NaBH4 (30.26 mg, 0.8 mmol) was added. Then the reaction mixture was stirred at room temperature for 30 minutes. All the solvent was evaporated and purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) to give title compound (6.5 mg, 15%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=3)[CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: Cc1oc(-c2cccc(-c3ccc(F)cc3)c2)nc1CCO
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54 mmol) (see Ex. 2, Part D) and para-fluorophenyl boronic acid (744 mg, 5.32 mmol) were stirred in n-PrOH (10 mL) under nitrogen, to which 2M Na2CO3 (3.54 mL) was added. The mixture was heated at 85° C., and after Pd(PPh3)4 (41 mg, 0.0354 mmol) was added, the reaction proceeded for 0.5 h. Once the reaction mixture had cooled to room temperature, it was concentrated and taken up in CH2Cl2 (20 mL), then washed with 0.5M NaOH (20 mL). The aqueous layer was back-extracted with CH2Cl2 (10 mL), combined organics were washed with 1M NaOH (10 mL), followed by H2O (10 mL), then dried over Na2SO4, and concentrated to a crude solid. Recrystallized from ethyl acetate:hexanes (1:1) and vacuum oven-dried at 50° C. to yield a tan solid (375 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.96 (d, J=7.6 Hz, 1H) 7.63–7.59 (m, 3H), 7.50 (t, J=7.6 Hz, 1H), 7.18–7.13 (m, 2H) 3.95 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.37 (s, 3H); MS (EI) 298.1 (M+H)+.
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:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[CH3:24][C:25]1([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][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])=[N:16][CH:17]=2)[CH2:28][O:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 8 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using 3-methyl-3-oxetanamine instead of methylamine, to the title compound (22 mg, 8%) which was obtained as a white solid. MS: m/e=380.2 [M+H]+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].Cl[C:12](=[CH:17][C:18]([F:21])([F:20])[F:19])[C:13]([F:16])([F:15])[F:14]>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[CH2:12][C:17]1([C:18]([F:21])([F:20])[F:19])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
11 g of pyrocatechol were dissolved in 200 ml of dimethylformamide, and 18 g of 45% strength by weight aqueous sodium hydroxide solution were added. 20 g of 2-chloro-1,1,1,4,4,4-hexafluoro-2-butene were added dropwise to the mixture at 75° C. The mixture was subsequently stirred at 75° C. for 30 minutes. It was then poured onto 500 ml of ice-water and extracted with diethyl ether. The organic phase was washed with water, dried with magnesium sulphate and concentrated. Finally, the product was distilled under a high vacuum. The yield was 15 g (=56%), and the boiling point was 60° C. under 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2[CH2:8][O:9][C:48](=[O:50])[NH:1][C:2]=2[N:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 154.1 %

Procedure:
To a cold (0° C.) solution of tert-butyl 1-[2-amino-6-[2-(benzyloxy)phenyl]-3-(hydroxymethyl)-4-pyridinyl]-2-phenylethylcarbamate (0.210 g, 0.400 mmol) in THF (3.0 mL) including triethylamine (0.167 mL, 1.199 mmol) was added dropwise a solution of triphosgene (0.059 g, 0.200 mmol) in THF (1.0 mL). After stirred at 0° C. for 45 min, the mixture was allowed to warm to room temperature, and the stirring was continued for 30 min. The reaction mixture was cooled at 0° C., and then quenched with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 2:1) to give tert-butyl 1-{7-[2-(benzyloxy)phenyl]-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl}-2-phenylethylcarbamate as a colorless oil (0.170 g, yield; 77%).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:27](Br)[CH3:28]>C(OCC)(=O)C.O>[CH2:27]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH3:28]
Reactant: CCBr
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1CC=C(c2c[nH]c3ccccc23)CC1
Reaction time: 5 h
Yield: 67.2 %

Procedure:
A mixture of 9.91 g of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 10.6 g of sodium carbonate, 150 ml of dimethylformamide and 4.5 g of ethyl bromide was stirred under an inert atmosphere at 30°-35° C. for 5 hours and was then poured into 1.5 liters of water which caused precipitation. The mixture was stirred for one hour and filtered and the filter was rinsed with water. The recovered product was dried overnight in an oven at 70° C. under reduced pressure in the presence of dehydrating agent to obtain 8.95 g of raw product melting at 205° C. The product was dissolved in 400 ml of refluxing ethyl acetate and the mixture was filtered hot. The filtrate was concentrated to 250 ml and crystallization was effected for one hour. The mixture was filtered and the recovered product was rinsed with ethyl acetate to obtain 6.28 g of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in the form of yellow crystals melting at 205° C. Concentration of the mother liquors yielded another 1.76 g of product after crystallization for a total yield of 8.04 g.