Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][O:37][CH2:38][CH2:39]Br>C(#N)C>[CH3:16][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C@@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH2:2][N:1]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:9][CH:8]=1
Reactant: BrCCOCCBr
Reactant: CCCC(C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(C)COc1ccc([C@H](CN2CCOCC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of (2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (100 mg, 0.271 mmol), prepared according to the procedure described in example 5, and potassium carbonate (75 mg, 0.543 mmol) in acetonitrile (4 mL) was added 2-bromoethyl ether (0.038 mL, 0.271 mmol). The reaction mixture was then heated at reflux for 18 h. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was then transferred to a separatory funnel containing water (20 mL) and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by HPLC (acetonitrile/water with 0.1% TFA) to afford (2S)-N-((1R)-1-(4-(2-methylpentyloxy)phenyl)-2-morpholinoethyl)-2-phenylpropanamide.TFA (55 mg, 37% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.25-7.39 (m, 5H), 6.97 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.36 (br. s., 1H), 4.83 (d, J=5.0 Hz, 1H), 3.74 (dd, J=8.8, 5.8 Hz, 1H), 3.61-3.69 (m, 2H), 3.49-3.61 (m, 4H), 2.34-2.56 (m, 4H), 2.23-2.30 (m, 2H), 1.83-1.95 (m, 1H), 1.52 (d, J=7.3 Hz, 3H), 1.26-1.50 (m, 3H), 1.12-1.22 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 439.3 [(M+H)+, calcd for C27H39N2O3 439.3].
Reaction SMILES: [N+](=C)=[N-].C[O:5][C:6](=[O:19])[C@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:8][C:9](=[O:11])[CH3:10]>>[C:9]([NH:8][C@H:7]([C:6]([OH:19])=[O:5])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: C=[N+]=[N-]
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A sample was treated with diazomethane to make the methyl ester before analysis. See Example 8 (N-acetyl phenylalanine methyl ester) for analytical details.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:23]([CH2:28][CH3:29])[C:24]([O:26][CH3:27])=[O:25]>CC#N>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:23]([CH2:28][CH3:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Br)C(=O)OC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCC(Oc1ccc(OCc2ccccc2)cc1)C(=O)OC
Yield: 91 %

Procedure:
A mixture of 4-benzyloxyphenol (30 g, 0.15 mol), cesium carbonate (58.6 g, 0.18 mol) and methyl 2-bromobutanoate (40.7 g, 0.22 mol) in CH3CN (350 mL) was kept at reflux for 20 hr. After cooling, the mixture was filtered and concentrated under reduced pressure and chromatographed over silica gel using AcOEt/hexanes to give the title compound 41.0 g (91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:13][C:12]2=[O:28])[CH:5]=1.[Br:30]NC(=O)CCC(N)=O>C(#N)C>[Br:30][C:13]1[C:12](=[O:28])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[Cl:10])[C:3]([O:2][CH3:1])=[O:29])[C:16]([CH3:17])=[CH:15][C:14]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:13][C:12]2=[O:28])[CH:5]=1
Reactant: NC(=O)CCC(=O)NBr
Agent: COC(=O)c1ccc(Cl)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1

Procedure:
methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoate was prepared by reacting methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (2.3 g, 5.47 mmol) with N-bromosuccinamide (0.97 g, 5.47 mmol) in acetonitrile (10 mL) at 0° C., using a similar procedure as described in step 3 of Example 465, to give 1.80 g (66.2%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.03 (m, 2H), 7.86 (d, J=9.70 Hz, 1H), 7.68 (q, J=7.62, 1H), 7.34 (dt, J=10.07, 2.46 Hz, 1H), 7.17 (dt, J=8.72, 2.90 Hz, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 1.91 (s, 3H). ES-MS m/z 495.9757 (M−H calcd for C21H14BrClF2NO4, requires 495.9795).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)Cl.[CH3:7][C:8]([C:10]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].CO>BrBr.O>[CH3:16][C:10]1([C:8]([CH2:7][Br:1])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)C1(C)CCCCC1
Reactant: BrBr
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C(=O)CBr)CCCCC1
Reaction time: 0.17 h

Procedure:
A solution of 328 g. bromine in 300 ml. chloroform was added gradually to a stirred solution of 300 g. 1-methylcyclohexyl methyl ketone in 100 ml. methanol. After the addition of a few drops of bromine solution at 15° C. the reaction mixture was cooled and maintained between 0° - 5° C. The reaction mixture was stirred for 10 minutes, after the addition of bromine had been completed, and then poured on to a mixture of crushed ice and water. The water layer was separated from the organic liquid and extracted with methylene chloride. The extract and the organic portion were combined and washed with water followed by a saturated solution of sodium bicarbonate and then finally with water. After drying over calcium chloride the liquid was evaporated and distilled to give bromomethyl 1-methylcyclohexyl ketone, b.p. 76° - 78° C./0.1 mm. Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1ccccn1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
A solution of 19.8 g (95 mmol) of 2-(N-(t-butyloxycarbonyl)aminomethyl)pyridine in anhydrous tetrahydrofuran was cooled under N2 atmosphere to 0° C. and treated with 4.95 g (124 mmol) of sodium hydride (60% dispersion in oil). The solution was stirred for 15 min, treated dropwise with 7.1 ml (114 mmol) of methyl iodide, stirred at ambient temperature for 2 h, and quenched cautiously with water. The resulting mixture was partitioned between ether and water, dried over Na2SO4, and concentrated in vacuo. Chromatography on silica gel provided 14.9 g (70%) of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:14])[CH:3]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:15]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[C:4]([F:14])[CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(NC2CCCCC2)cc1F
Yield: 67.9 %

Procedure:
A solution of compound (7) (1.50 g, 7.6 mmol), cyclohexanone (1.57 mL, 15.2 mmol), and NaBH3CN (0.96 g, 15.2 mmol) in methanol (10 mL) and acetic acid (0.2 mL) was allowed to undergo conventional reactions, followed by the same reactions and treatments as those in Example 3. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 1.37 g (65%) of compound (11b) of interest as brown powder.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11]2>CO.C(OCC)(=O)C>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([OH:17])[CH2:12][CH2:11]2
Reactant: O=C1CCc2cc(-c3cccs3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1CCc2cc(-c3cccs3)ccc21
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a slurry of sodium borohydride (0.22 g, 5.86 mmol) in methanol (6mL) at 0° C. was added a solution of 5-(2-thienyl)-2,3-dihydro-1H-inden-1-one (0.50 g, 2.34 mmol ) in methanol (2 mL). The reaction was slowly warmed to room temperature and stirred until the reaction was completed as monitored by thin layer chromatography (4 h). The reaction mixture was carefully quenched with 1.0 N aqueous hydrochloric acid at 0° C. until a clear solution was obtained. Diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride (brine), and dried over anhydrous magnesium sulfate. Filtration, concentration and column chromatography on silica (7:3 hexanes/ethyl acetate) gave 5-(2-thienyl)-2,3-dihydro-1H-inden-1-ol (0.30 g, 59% yield) as solid. 1H NMR (400 MHz, CDCl3): 7.48 (m, 2H), 7.38 (br d, 1H), 7.26 (m, 2H), 7.08 (dd, 1H), 5.21 (t, 1H), 3.04 (m, 1H), 2.80 (m, 1H), 2.50 (m, 1H), 2.10 (brs, 1H), 1.93 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(Cc1ccncc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.366 mmol) of (2R*,4S*)-2-benzyl-1-(4-pyridylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 55 mg (1.46 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR45## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.3 1, FD-MS: M+ =450.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>CCCCCCC.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: CC(CBr)c1ccccc1
Solvent: CCO
Solvent: CCCCCCC
Product: Cc1nc(-c2ccn(C[C@@H](C)c3ccccc3)n2)sc1C(=O)NCc1cccnc1
Yield: 15 %

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-bromo-1-methyl-ethyl)benzene as described in Example 49 and isolated by chiral separation (80/20 heptane/ethanol) (0.0033 mg, 15% yield). 1HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.18-7.34 (m, 4H), 7.13 (d, J=8 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.12-6.20 (m, 1H), 4.63 (d, J=4 Hz, 2H), 4.18-4.38 (m, 2H), 3.37-3.46 (m, 1H), 2.75 (s, 3H), 1.30 (d, J=8 Hz, 3H); MS (M+H)+=418.4; Rt=1.31 min; HRMS (M+H)+=418.17.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:33]=[O:34])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)c(Cl)n2)cn1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (568, 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, and then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C., followed by adding tert-butyllithium (1.70 M in hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158 mol) was added and the reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 350%, to 100% ethyl acetate in hexane to give a light yellow solid (569, 2.84 g, 71.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:43])[C:32]3[N:36]=[C:35]([CH:37]4[CH2:41][CH2:40][O:39][CH2:38]4)[NH:34][C:33]=3[CH:42]=2)[CH:23]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:43])[C:32]6[N:36]=[C:35]([CH:37]7[CH2:41][CH2:40][O:39][CH2:38]7)[NH:34][C:33]=6[CH:42]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CCOC3)nc12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C6CCOC6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
28 mg (0.10 mmol) 7-methoxy-3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, 33 mg (0.10 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 30 μL (0.20 mmol) DIPEA in 2.0 mL DMF were stirred at 50° C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 4 M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34](=[O:50])[N:35]([C:48]#[CH:49])[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1)([CH3:32])([CH3:31])[CH3:30].CCOC(C)=O.O>CN(C=O)C>[C:29]([O:33][C:34](=[O:50])[N:35]([C:48]1[N:23]([C:12]2[CH:11]=[C:10]([CH:26]([CH3:28])[CH3:27])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]=[N:25][CH:49]=1)[C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)=[CH:40][CH:41]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(-n2nncc2N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (373 mg, 1 mmol) and ethynyl-(4-morpholin-4-yl-phenyl)-carbamic acid t-butyl ester (275 mg, 0.91 mmol) in DMF (2.5 ml) was flushed with nitrogen three times as previously described before adding [Cp*Ru]4 (49 mg, 0.045 mmol) and repeating the three cycle-degassing with nitrogen. The reaction mixture was stirred at RT until completion (i.e., monitored by TLC). AcOEt and H2O were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (once) and dried over Na2SO4. The solvent was removed under reduced pressure and the reaction mixture was purified by column chromatography (PE/AcOEt:60/40). The title compound was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH2:40][CH2:41][F:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH2:40][CH2:41][F:42])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: FCCCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OCCCF)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].I[C:22]1[CH:23]=[C:24]([CH3:29])[C:25]([CH3:28])=[CH:26][CH:27]=1.N1CCCC1.CO>C(Cl)(Cl)Cl.[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>[CH3:29][C:24]1[CH:23]=[C:22]([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[C:11]([NH2:20])[C:10]=3[N:9]=[CH:8]2)[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: Cc1ccc(I)cc1C
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: C1CCNC1
Solvent: CO
Product: Cc1ccc(C#CCOCCn2cnc3c(N)nc4ccccc4c32)cc1C
Temperature: 25 °C
Yield: 14.2 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol), copper (I) iodide (0.036 g, 0.2 mmol), 4-iodo-ortho-xylene (0.5 g, 2.1 mmol) and pyrrolidine (10 mL) were combined and stirred at ambient temperature. Dichlorobis(triphenylphosphine)palladium(II) (0.066 g, 0.1 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. Analysis by TLC (30% methanol in chloroform) indicated that starting material was still present. The reaction mixture was heated at 65° C. overnight. The pyrrolidine was removed under reduced pressure. The resulting residue was triturated with dichloromethane containing methanol. The insoluble material was isolated by filtration and then recrystallized from toluene (40 mL) to provide 0.1 g of 1-(2-{[3-(3,4-dimethylphenyl)-2-propynyl]oxy}ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 214-216° C. Analysis: Calculated for C23H22N4O: % C, 74.57; % H, 5.99; % N, 15.12. Found: % C, 74.24; % H, 5.98; % N, 15.08.
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][OH:14].[Br:15][C:16]1[N:17]=[N:18][C:19](Br)=[CH:20][CH:21]=1>>[Br:15][C:16]1[N:17]=[N:18][C:19]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][CH:21]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Brc1ccc(Br)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(Br)nn1
Yield: 89 %

Procedure:
As described for example 1, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (2.46 g, 13 mmol) was converted using 3,6-dibromopyridazine instead of 3,6-dichloropyridazine to the title compound (3.99 g, 89%) as a white solid. MS: m/e=348.0/346.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=2[Cl:26])=O)[C:3]=1[N+:32]([O-])=O>CC(O)=O.CCOC(C)=O.[Fe]>[C:27]([C:24]1[C:25]([Cl:26])=[C:21]([C:19]2[NH:32][C:3]3[C:4](=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:17])([F:16])[F:15])=[N:7][C:2]=3[CH3:1])[N:18]=2)[N:22]([CH3:31])[N:23]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide (138 mg, 0.278 mmol, prepared as described in STEP A above) in AcOH (10 mL) was treated with iron powder (77.5 mg, 1.39 mmol), and the mixture was heated to 100° C. for 4 h. The cooled mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted again with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:9 for 15 min, then 1:9 to 2:3 over 40 min) to yield 8-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-methyl-2-(2-trifluoromethyl-phenyl)-7H-purine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.66 (br. s., 1H), 7.82 (d, J=7.6 Hz, 1H), 7.72-7.77 (m, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.54-7.62 (m, 1H), 4.40 (s, 3H), 2.95 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C21H20N6ClF3: 449.1 (M+H); Measured: 449.1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)cc1
Reaction time: 6 h
Yield: 9.8 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added p-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg,0.68 mmol) and triethylamine (0.68, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (12.8 mg, 10%).