Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(=O)O[CH2:29][CH2:28][O:27]1>>[OH:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Reactant: O=C1OCCO1
Product: OCCOc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
First, 19.2 g (60 mmol) of the HQ obtained in section (M) mentioned above was put in an 1-liter three-necked flask, and dissolved by the addition of 500 ml of sulforane. To this solution, 7.92 g (90 mmol) of ethylene carbonate was added, and the mixture was heated under a nitrogen atmosphere. Then 0.1 g of K2C03 was added at the reflux temperature of sulforane, and reflux was continued for 4 hours with stirring. After the reaction was completed, the reaction mixture was filtered and the filtrate was cooled. The white solid that was precipitated was collected by filtration and dried. In this way, 18.38 g (yield, 83% of 4-(2-hydroxyethoxy)-p-quaterphenyl (HEQ) was obtained. The liquid-crystal transition temperature of HEQ was 335° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)#[N:14]>ClCCl.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h
Yield: 28.5 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) in dry dichloromethane (20 ml) and triethylamine (0.7 ml) was treated slowly with a solution of 4-cyanobenzoyl chloride (0.50 g) in dry dichloromethane (30ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were then washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (Na2SO4) and evaporated to give a colourless oil which was crystallised from ethyl acetate/isohexane to afford 1-(4-pyridyl)4-(4-cyanobenzoyl)piperazine (0.25 g) as a solid, m.p. 164-165° C.; microanalysis, found: C, 69.7; H, 5.6; N, 18.5%; C17H16N4O requires: C, 69.8; H, 5.52; N, 19.2%; NMR: (CDCl3) 3.38(bs,4H), 3.75(bs,4H), 6.67(dd,2H), 7.56(dd,2H), 7.76(dd,2H), 8.32(dd,2H): MS: m/z 293 (MH)+.
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:44])[CH2:9][N:10]([C:16](=[O:43])[C@H:17]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])[NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([O:32][CH3:33])[CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:11][CH2:12][S:13][CH2:14][CH3:15])(C)(C)C>FC(F)(F)C(O)=O>[N:1]#[N:2].[CH3:33][O:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:34][CH3:35])[CH:23]=[C:22]([S:19]([NH:18][C@H:17]([C:16]([N:10]([CH2:11][CH2:12][S:13][CH2:14][CH3:15])[CH2:9][C:8]([OH:44])=[O:7])=[O:43])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])(=[O:21])=[O:20])[CH:31]=[CH:30]2
Reactant: CCSCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: CCSCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1

Procedure:
A solution of 5.0 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine tert-butyl ester in 10 ml of trifluoroacetic acid was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with ethanol-H2O-NH4OH (5:4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[C:15]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:16]=1[C:17](O)=[O:18])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:17]([C:16]1[CH:20]=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:23][C:15]=1[N:14]([CH2:28][CH3:29])[CH2:12][CH3:13])=[O:18])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-diethylamino-5-methanesulfonyl-benzoic acid (example 2.6).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:5].[Si:15]([O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.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>CN(C=O)C.C(OCC)(=O)C>[Si:15]([O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:5])=[O:36])([C:28]([CH3:30])([CH3:31])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: NCC(=O)c1cccc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 2-amino-1-(3-nitrophenyl)ethanone HCl salt (300 mg, 1.38 mmol) and 3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethylpropanoic acid (543 mg, 1.52 mmol) in DMF (1.3 mL) was added HATU (579 mg, 1.52 mmol) and the mixture was cooled to 0° C. Hunig's base (726 μL, 4.15 mmol) was added, and the mixture was stirred for two hours at this temperature. The mixture was diluted with ethyl acetate (30 mL), then washed with 1:1 water:saturated NaHCO3(aq) (30 mL) and 1:1 water:brine (2×30 mL). The aqueous fractions were further extracted with ethyl acetate (30 mL), then the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 680 mg of 3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-N-[2-(3-nitrophenyl)-2-oxoethyl]propanamide (1.31 mmol, 95%) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.CCCCCC.C([Li])CCC.[C:19](=[O:21])=[O:20].O.Br[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([OH:21])=[O:20])=[N:25][CH:26]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a toluene solution (300 ml) at −78° C. in which 2,5-dibromopyridine (4.7 g) was dissolved, n-butyl lithium hexane solution (1.6 M) was added dropwise, followed by stirring at −78° C. for 3 hours. To the reaction mixture, dry ice (ca. 50 g) was added, and followed by further stirring at room temperature for 10 hours. Water (100 ml) was added, and the aqueous layer washed with ethyl acetate (100 ml×2) was neutralized with 5M−HCl aqueous solution under ice cooling, and the resulting precipitate was filtered and dried, to obtain 5-bromo-pyridine-2-carboxylic acid as a colorless powder (2.0 g, 50%). Then, 5-bromo-pyridine-2-carboxylic acid (202 mg), N-methylpiperazine (124 μl), WSCI (230 mg), HOBt (149 mg) and triethylamine (140 μl) were dissolved in acetonitrile (10 ml), followed by stirring at room temperature for 10 hours. To the reaction mixture, water (10 ml) was added, followed by extraction with ethyl acetate (10 ml). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (dichloromethane), to obtain (5-bromo-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone as a yellow oil (70 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[C:5]#[N:6].Cl.[NH2:16][OH:17].C(N(C(C)C)C(C)C)C>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:12])([F:13])[F:14])/[C:5](=[N:16]/[OH:17])/[NH2:6]
Reactant: N#Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: N/C(=N\O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzonitrile (1.0 g, 4.51 mmol) and hydroxylamine hydrochloride (1.5 eq, 0.47 g, 6.77 mmol) in ethanol (10 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.6 eq, 1.26 ml, 7.22 mmol) and refluxed at 80° C. for 12 hours under N2. Allow to cool to rt. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), dry, concentrate in vacuo afforded (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (0.71 g, 62.1%, white solid). Used crude in the next step. HRMS(B) m/z 254.0070
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[NH2:22])[CH2:12]2)[CH2:8][CH2:7]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:27]([N:35]=[C:36]=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:1]([N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[NH:22][C:36]([NH:35][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[S:37])[CH2:12]2)[CH2:8][CH2:7]1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1NC(=S)NC(=O)c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 20f (118 mg, 0.33 mmol) and benzoylisothiocyanate (63 μL, 0.47 mmol) in DCM (3 mL) was stirred at rt for 3 h. The reaction was concentrated and the residue was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to give 20g, as yellow solid (156 mg). LC-MS m/z 513.06 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][OH:20])[CH:13]([CH3:27])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5].O1CCOCC1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[NH4+].[Cl-]>C1(C)C=CC=CC=1.O=[Mn]=O.CCOCC>[F:29][C:2]([F:1])([F:28])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][OH:20])[C:13]([CH3:27])=[CH:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1C(CO)c1ccccc1
Agent: O=[Mn]=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1C(CO)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A solution of 40 mg (0.094 mmol) 1,1,1,3,3,3-hexafluoro-2-[1-(2-hydroxy-1-phenyl-ethyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-propan-2-ol (example 70) in 1 mL of toluene was treated with 45 mg (0.47 mmol) of MnO2. After stirring at 80° C. for 8 hrs, 0.5 mL of dioxane and 22 mg (0.094 mmol) of DDQ were added. The resulting mixture was stirred at RT overnight and poured into a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 2:1 yielded 15 mg (38%) of 1,1,1,3,3,3-hexafluoro-2-[1-(2-hydroxy-1-phenyl-ethyl)-2-methyl-1H-indol-5-yl]-propan-2-ol, brown oil, MS: 418 (MH+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:38]=[C:39]=[O:40])(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:39](=[O:40])[NH2:38])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Example 66 (488 mg, 1.00 mmol) in dichloromethane (10 ml) was added trimethylsilylisocyanate (2.00 ml), and the mixture was stirred at room temperature for 3 days. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (20 ml) and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (20 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the mixture was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (353 mg, 0.66 mmol, Yield 66%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCBr
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC)c(O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5 g (27.2 mmol) of 3,4-Dihydroxy-benzoic acid ethyl ester was dissolved in 100 ml DMF and 3.75 g (27.2 mmol) of potassium carbonate was added. The solution was cooled to 0° C. and a solution of 2.96 g (27.2 mmol) ethyl bromide in 10 ml DMF was added dropwise. The solution was stirred for 16 h at room temperature (RT). The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)C>O1CCOCC1.C(OCC)C.[Pt](=O)=O>[N:25]1([C:16]2[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=2[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH2:4][CH2:3][NH:2][CH2:1]3)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(-n2ccnc2)c1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.049 g, 0.069 mmol), isoquinolin-5-ylboronic acid (Frontier Scientific, Logan, Utah, 0.297 g, 1.718 mmol), 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (0.400 g, 1.374 mmol), and potassium phosphate (1.167 g, 5.50 mmol) in 6 mL dioxane 3 mL water was heated to 120° C. overnight. The reaction mixture was diluted with diethyl ether. The organics were separated and concentrated. The resulting residue was taken up in 6 mL MeOH, was treated with platinum(IV) oxide (0.031 g, 0.137 mmol) and acetic acid (0.236 ml, 4.12 mmol) and was placed under 45 psi (4559.6 kpa) H2 for 2 hours. The reaction mixture was filtered through a plug of diatomaceous earth eluting with EtOAc. The filtrate was washed with saturated NaHCO3 solution, the organics dried over MgSO4 and concentrated yielding 5-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.450 g, 1.311 mmol). [M+H]+=344.0
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:28]([C:20]1[CH:21]=[C:22]2[C:27](=[C:18]([C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH:19]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(COc2cccc(-c3cc(C(C)C)cc4cccnc34)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2cccc(OCc3ccc(C(=O)O)cc3)c2)c2ncccc2c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the ester of EXAMPLE 9 (1.0 eq) in THF/MeOH (2/1; 0.1M) was added of aqueous solution of LiOH (1N; 5.0 eq). The resulting mixture was stirred 1 hour at 70° C., acidified to pH 5 using HCl (1N) and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 15 min) afforded the title compound as a white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>O1CCCC1>[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:18]1[CH:17]=[CH:16][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([O:13][CH3:12])[C:19]=1[O:20][CH3:21]
Reactant: BrCCCCCCBr
Agent: COc1cccc(-c2ccccc2)c1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(CCCCCCBr)ccc(-c2ccccc2)c1OC
Reaction time: 2.5 h

Procedure:
A solution of 2.5M butyl lithium in hexane (16 mL, 0.04 mol) was added dropwise over 15 min. to a stirred solution of 8.3 g (0.039 mol) of 2,3-dimethoxybiphenyl [J. M. Bruce and F. K. Sutcliffe, J. Chem. Soc. 4435 (1955)] in 160 mL of anhydrous tetrahydrofuran cooled at 0° under argon. The reaction mixture was stirred at 0° for 2.5 hours and then refluxed for 30 min. After cooling to 5°, 6.3 mL (0.039 mole) of 1,6-dibromohexane was added. Stirring was continued at 5° for 30 min., at 25° for 30 min. and at reflux for 20 hours. Workup as in Example 1 gave an oil. Purification by HPLC using 3% ethyl acetate-hexane gave 5.7 g of unreacted 2,3-dimethoxybiphenyl and 3.3 g of 4-(6-bromohexyl)-2,3-dimethoxy-1,1'-biphenyl as an oil. The structure was confirmed by the nmr and mass spectra (molecular ion at m/e 376).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CCOc1c(NC(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a room temperature solution of 5.81 g (34 mmol) of 3,4-diethoxy-3-cyclobutene-1,2-dione and 50 mL of THF was added 2.9 g (34 mmol) of tert-butyl amine. After stirring at room temperature for 12 hours, the reaction mixture was evaporated to a yellow oil. Flash chromatography on silica gel, eluting with 0 to 5% MeOH/CH2Cl2 gave 6.2 g (34 mmol, a 100% yield) of the title compound as a white solid: mp: 80°-82° C.; 1H NMR: (300 MHz, DMSO-d6): δ1.30-1.62 (m, 12H), 4.70-4.93 (m, 2H), 5.50-6.42 (brm, 1H); IR (KBr, cm-1): 3214w, 3144m, 3071w, 2973m, 2941m, 1794m, 1702s, 1606s, 1577s, 1500-1442brs; MS (CI) m/z (relative intensity): 198 (M+H, 100); Anal. Calcd. for C10H15NO3 : C, 60.90; H, 7.67; N, 7.10. Found: C, 61.03; H, 7.66; N, 6.98.
Reaction SMILES: C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.[Mg+2].[C@H:28]1([NH:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:48])[CH:44]=3)[N:39]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.[CH3:49][C:50]1[C:54]([N:55]=[C:56]=[O:57])=[C:53]([CH3:58])[O:52][N:51]=1>>[CH3:49][C:50]1[C:54]([NH:55][C:56]([NH:48][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[C:38]([NH:37][C@H:28]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]2)[CH:47]=[CH:46]3)=[O:57])=[C:53]([CH3:58])[O:52][N:51]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Mg+2]
Product: Cc1noc(C)c1NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=414.6 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 3,5-dimethylisoxazol-4-yl isocyanate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O
Reactant: COC(=O)CCCCBr
Product: COC(=O)CCCCOc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
Prepared in an analogous manner to example 11 from intermediate 7 and methyl 5-bromopentanoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)[N:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[N:3]=1
Reactant: Nc1nc(NCc2ccc(OCc3ccccc3)cc2)nc2nc(-c3ccco3)nn12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc(NCc2ccc(O)cc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-5-[(4-benzyloxyphenyl)methyl]amino-2-(2-furyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine (2.37 g) in ethyl acetate (150 ml) and methanol (150 ml) was treated with 10% palladium on carbon (3.0 g) and hydrogenated at atmospheric pressure for 2.5 hours. The catalyst was filtered through diatomaceous earth and the liquors evaporated. The residue was purified by chromatography on silica (100 g) eluting with dichloromethane containing methanol 3-30% v/v, and gave 7-amino-2-(2-furyl)-5-[(4-hydroxyphenyl)methyl]amino-[1,2,4]-triazolo[1,5-a][1,3,5]triazine, m.p. 268-270; NMR: 4.39 (d, 2H, CH2N), 6.64 (d of d, 1H, furyl-4H), 6.68 and 7.13 (A2B2 pattern, 4H, phenyl-H), 7.03 (d, 1H, furyl-3H), 7.8 (t, 1H, NH), 7.84 (d, 1H, furyl-5H), 8.13 (br s, 2H, NH2) and 9.19 (s, 1H, OH); m/e 324 (M+H)+.