Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][C:32]#[CH:33]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:34]1([CH2:30][CH2:31][C:32]#[C:33][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#CCCc1ccccc1
Reactant: Clc1nc2ccccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1nc2ccccc2o1)CCc1ccccc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 40.5 %

Procedure:
To a solution of CuI (15 mg, 81 mmol) in triethylamine (3 mL) were added 2-chlorobenzo[d]oxazole (250 mg, 1.63 mmol), (PPh3)2PdCl2 (57 mg, 81 μmol), triphenylphosphine polymer bound 3 mmol/g (98 mg, 293 μmol) and a solution of 1-(but-3-ynyl)benzene (250 mg, 1.92 mmol) in DMF (0.5 mL). The reaction mixture was stirred for 25 min. at 120° C. in the microwave cavity. The reaction was quenched as described in Example 1. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 163 mg (0.66 mmol, 40%) of 2-(4-phenylbut-1-ynyl)benzo[d]oxazole as an orange oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:22]=[CH2:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCO.CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Yield: 62.6 %

Procedure:
To a solution of 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10%, 0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h. The catalyst was removed by filtration, the filtrate was concentrated to dryness and the resulting residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:1, v/v) to afford the title compound (0.32 g, 64%) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.52 (d, 1H, J=7.6 Hz), 7.39-7.2 (m, 10H), 6.41 (d, 1 h, J=7.6 Hz), 5.18 (s, 2H), 5.15 (s, 2H), 2.58 (q, 2H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz), ER-MS m/z=320 (MH+) HR-MS m/z calcd C21H22NO2 320.1651, found 320.1648.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:22]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
1-Bromo-4-chloro-2-nitro-benzene (7.00 g, 29.60 mmol) was dissolved in DMF to which K2CO3 (5.11 g, 37.01 mmol) and 3-Hydroxy-benzoic acid methyl ester (4.95 g, 32.57 mmol) were added. The reaction mixture was then heated to 100° C. for 2 h the reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. Solvent dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. (7.2 g, 79%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.FC(F)(F)S(O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([N:33]([CH3:44])[CH:34]3[CH2:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]3)=[N:31][N:32]=2)=[C:24]([O:45][CH3:46])[CH:23]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:46][O:45][C:24]1[CH:23]=[C:22]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[S:29][C:30]([N:33]([CH3:44])[CH:34]2[CH2:39][C:38]([CH3:40])([CH3:41])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]2)=[N:31][N:32]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
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: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177 mg, 0.849 mmol) and 3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl trifluoromethanesulfonate (332 mg, 0.653 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (38 mg, 0.033 mmol) followed by a solution of Na2CO3 (208 mg, 1.958 mmol) in water (1 mL). The resulting mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic phase was separated, dried over MgSO4, and filtered. To the filtrate was added SiliaMetS DMT (541 mg, 0.61 mmol/g, 0.33 mmols) and the resulting suspension stirred at room temperature for 18 hours. The SiliaMetS DMT was removed by vacuum filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to afford the crude product as a pale yellow solid. The crude material was recrystallized from MeOH (3 mL) to afford the title compound as a white solid (0.166 g, 57% yield). LC-MS: Rt 0.86 min; MS m/z 441.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.37 (d, J=1.52 Hz, 1H), 7.29 (dd, J=8.59, 1.52 Hz, 1H), 4.35 (tt, J=12.38, 3.28 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 2.97 (s, 3H), 1.61 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz, 2H), 1.26 (s, 1H), 1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.60 min; MS m/z 440.4 [M+H]+ [Method B]. HR-MS: Rt 1.43 min; MS m/z 441.2419 [M+H]+ [Method C].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:28][OH:29].C([O-])([O-])=O.[Na+].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=[N:28][OH:29])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCC(=NO)CC2
Reaction time: 8 h

Procedure:
3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione (0.1, 0.29 mmol, 1 equiv) was combined with hydroxylamine hydrochloride (40 mg, 0.58 mmol, 2 equiv) and aqueous Na2CO3 (0.5 mL) in a mixture of MeOH (10 mL) and water (1 mL). The mixture was stirred overnight. Then the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 362 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.15-8.13 (d, J=7.80 Hz, 1H), 7.76 (s, 1H) 7.64-7.59 (d, J=8.10 Hz, 1H), 7.52-7.48 (m, 3H), 7.36-7.33 (m, 1H), 4.46-4.35 (m, 2H), 3.15-3.08 (m, 2H), 2.84-2.73 (m, 2H), 2.59-2.55 (m, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: ++.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][C:25]=2[OH:26])[O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([NH:19][C:20]#[N:21])=[CH:14][C:13]=2[CH3:22])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([O:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([NH:19][C:20]4[NH:29][N:28]=[N:27][N:21]=4)=[CH:14][C:13]=3[CH3:22])[CH:23]=[CH:24][C:25]=2[OH:26])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1cc(NC#N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(Nc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Temperature: 140 °C

Procedure:
2-Cyclopropylmethanesulfonyl-4-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-phenol was prepared from 4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-cyanamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.5 equiv) and ammonium chloride (10 equiv) were used, and the reaction was heated to 140° C. for 20 hours. After the reaction had been acidified, the aqueous mixture was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with aqueous 1N HCl (3×50 ml), and brine (50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane=15:1.5:83.5) to afford the title product of Example 7. MS (APCI−) Calc.: 415.1, Found: 413.8 (M−1).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:4].[NH4+:32].C([O-])(=O)C>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:7]3[C:6](=[CH:11][CH:10]=[C:9]([C:12](=[O:20])[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)[CH:8]=3)[NH:5][C:3](=[O:4])[N:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: [NH4+]
Reactant: Cc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A mixture of intermediate 21 (0.0085 mol) and acetic acid, ammonium salt (0.0169 mol) in DMSO (42 ml) was stirred at 60° C. for 4 hours then cooled and poured out into ice water. The precipitate was filtered, washed with water, taken up in warm CH3CN, filtered off and dried under a vacuo, yielding 2.02 g (63%) of 4-(3-chlorophenyl)-6-(4-methylbenzoyl)-2(1H)-quinazolinone (intermediate 22), mp.>260° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[CH:6]=1)[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:7]([F:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
A mixture of 5 g (27 mmol) 3,4-Difluoro-benzoic acid ethyl ester and 11.56 g (134 mmol) piperazine in 15 ml N,N-dimethylacetamide was heated to 120° C. for 1.5 h and subsequently all volatiles were removed under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/methanol to yield 6.19 g (91%) of the title compound as white amorphous solid.
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][NH:19][CH3:20]>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][N:19]([CH3:20])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1nc2cc([N+](=O)[O-])ccc2o1
Yield: 44.5 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Preparation 139, using 2-methylsulfanyl-5-nitro-benzooxazole (5.0 g, 23.8 mmol) and N,N,N′-Trimethyl-ethane-1,2-diamine (15.4 mL, 118.9 mmol) at 140° C. The product is purified by silica gel flash column chromatography (330 g column, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (2.8 g, 44%). MS (ES+) 265.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([OH:26])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.O[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([O:26][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccccn1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Oc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a stirred suspension of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylic acid (prepared according to the procedure described in WO 2007/079162, 1.50 g, 3.30 mmol) in dichloromethane (15 mL) at room temperature was added oxalyl chloride (0.58 mL, 6.60 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was dissolved in dichloromethane (10 mL) and added to a stirred suspension of 2-hydroxypyridine (0.38 g, 3.96 mmol) and K2CO3 (1.37 g, 9.90 mmol) in dichloromethane (15 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a short pad of Celite® diatomaceous filter aid, and the pad was rinsed with dichloromethane. The combined filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title product as a yellow solid (0.80 g, 46% yield).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=2)[N:14]([CH2:22][C:23]2[CH:28]=[C:27]([Br:29])[C:26]([Br:30])=[C:25]([Br:31])[CH:24]=2)[C:13](=[O:32])[CH:12]=1)C1C=CC=CC=1.C(O)C.Cl>O1CCOCC1.[Pd]>[OH:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=2)[N:14]([CH2:22][C:23]2[CH:28]=[C:27]([Br:29])[C:26]([Br:30])=[C:25]([Br:31])[CH:24]=2)[C:13](=[O:32])[CH:12]=1
Reactant: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1cc(CCO)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Yield: 71 %

Procedure:
A solution of 4-(2-benzyloxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline (6.0 g.) in a mixture of dioxan (50 ml.), ethanol (50 ml.), and concentrated hydrochloric acid (2 ml.) was hydrogenated at atmospheric pressure over 5% palladium on carbon (1 g.). The theoretical quantity of hydrogen (390 ml. at N.T.P.) was absorbed in four minutes. The hydrogenation was stopped and the mixture filtered. Evaporation of the filtrate gave the crude product which was recrystallised twice from methanol to give 4-(2-hydroxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline, m.p. 199°-201° C., in 71% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]1([NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Cc1cccc(O)c1)Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1cccc2ccccc12
Yield: 47.9 %

Procedure:
A mixture of 2-(3-hydroxyphenyl)-N-naphthylacetamide (5.00 g, 18.03 mmol), benzyl bromide (3.76 g, 220 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in acetone (50 mL) was heated to reflux overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (3.176 g, 48% yield): 1H NMR (DMSO-d6) 10.13 (br, 1H), 8.06 (m, 1H), 7.94 (m, 1H), 7.77 (d, 1H), 7.67 (d, 1H), 7.26-7.56 (m, 9H), 6.92-7.11 (m, 3H), 5.11 (s, 2H), 3.79 (s, 2H); ES-MS (m/z) 368 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1>O1CCCC1>[F:25][C:24]([F:27])([F:26])[C:20]1[N:19]=[C:18]([O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (0.88 g, 60% in mineral oil, 22 mmol) in tetrahydrofuran (50. mL) at 0° C. was added tert-butyl 4-hydroxypiperidine-1-carboxylate (4.4 g, 22 mmol, Aldrich). The mixture was stirred at room temperature for one hour. A solution of 2-chloro-6-(trifluoromethyl)pyridine (2.0 g, 11 mmol, Oakwood) in tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 2 days. The mixture was quenched by the addition of water, and the product was extracted with EtOAc. The extract was washed with water, followed by brine, was dried over sodium sulfate, filtered and concentrated. Flash chromatography on a 120 g silica gel cartridge, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (3.8 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.75-7.64 (m, 1H), 7.23 (d, J=7.3 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.27 (tt, J=7.7, 3.7 Hz, 1H), 3.83-3.66 (m, 2H), 3.31 (ddd, J=13.4, 8.5, 3.7 Hz, 2H), 1.99 (ddt, J=13.3, 6.9, 3.7 Hz, 2H), 1.73 (dtd, J=12.3, 8.1, 3.9 Hz, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −68.94 (s). LCMS (M-tBu+H)+: 291.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[CH3:30][C@H:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:15])=[O:16]
Reactant: NCCc1ccc(O)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CNCCN1S(=O)(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 153 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.6 (d, 1H) 8.5 (d, 1H) 8.3 (d, 1H), 8.1 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.1 (d, 2H), 6.6 (d, 2H), 3.9-3.8 (m, 3H), 3.4-3.3 (m, 2H), 3.2-3.1 (m, 3H), 3.0-2.9 (m, 3H), 1.2 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[C:29]2[N:28]=[CH:27][C:26]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)=[N:25][C:24]=2[C:23]([C:39](O)=[O:40])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39]([C:23]2[C:24]3[N:25]=[C:26]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]4)[CH:27]=[N:28][C:29]=3[C:20]([C:10]3[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=3[Cl:19])=[CH:21][CH:22]=2)=[O:40])[CH:3]=1
Reactant: CCN1CCN(Cc2cnc3c(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc(C(=O)O)c3n2)CC1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2cnc3c(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc(C(=O)Nc4cccnc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-aminopyridine, 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylic acid (Step 82.1) and stirring the reaction mixture for 12 h at rt. Title compound: ESI-MS: 581.0/583.2 [M+H]+; tR=3.24 min (System 1); TLC: Rf=0.38 (DCM/MeOH, 9:1).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:5]=2[O:4]1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH:3]([CH2:2][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:7][C:6]=2[CH:8]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc2c(c1)CC(CI)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Yield: 51.4 %

Procedure:
To a solution of 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran (2.8 g, 8.5 mmol) in CH3CN (40 ml) was added potassium carbonate (2.36 g, 17.1 mmol, 2 eq) and piperazine (2.94 g, 34.1 mmol, 4 eq) at room temperature. The mixture was heated at reflux for 3 h, then solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-2.5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine as light yellow oil (1.25 g, 51%); (ES, m/z): [M+H]+ 287; 1H NMR (300 MHz, CDCl3): δ 7.37 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.00-5.10 (m, 1H), 3.26-3.35 (m, 1H), 2.96-3.04 (m, 1H), 2.88-2.95 (m, 4H), 2.78-2.80 (m, 1H), 2.54-2.69 (m, 4H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11]Br.[OH-].[K+]>CO>[Br:9][CH2:10][CH2:11][O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cccc(OCCBr)c1

Procedure:
A mixture of resorcinol (88 g), 1,2-dibromoethane (180 g) and potassium hydroxide (44.8 g) was stirred under reflux in methanol (600 ml) for 24 hours. The reaction mixture was cooled. The residual solid was removed by filtration and the filtrate was evaporated to give 3-(2-bromoethoxy)phenol as an oil which was essentially pure as indicated by thin layer chromatography (tlc) [using silica plates and 10% v/v methanol in dichloromethane as eluant] and was used without purification.