Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14](Br)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][C:29]1[CH:33]=[C:32]([NH2:34])[S:31][N:30]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14]([NH:34][C:32]3[S:31][N:30]=[C:29]([CH3:28])[CH:33]=3)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(nc1Br)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Reactant: Cc1cc(N)sn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc3c(C(=O)NC(C)(C)C)cn(COCC[Si](C)(C)C)c3nc2C)sn1
Temperature: 110 °C
Reaction time: 19 h
Yield: 42.6 %

Procedure:
A mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.221 g, 0.5 mmol), 3-methyl-isothiazol-5-ylamine hydrochloride (0.151 g, 1 mmol), tris(dibenzylideneacetone)dipalladium (0.023 g, 0.025 mmol), racemic BINAP [rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl](0.047 g, 0.075 mmol) and sodium tert-butoxide (0.144 g, 1.5 mmol) in toluene (3.5 mL), under an argon atmosphere, was heated and stirred in a sealed vessel at 110° C. for 19 h. The cooled reaction mixture was diluted with ethyl acetate, washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 75% ethyl acetate in hexanes, then repeated with 50% ethyl acetate in hexanes, and again with 40% ethyl acetate I hexanes) gave 3-methyl-2-(3-methyl-isothiazol-5-ylamino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.101 g, 43%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 9H), 0.84 (t, J=8.0 Hz, 2H), 1.55 (s, 9H), 2.35 (s, 3H), 2.67 (s, 3H), 3.53 (t, J=8.0 Hz, 2H), 5.61 (s, 2H), 6.94 (s, 1H), 7.34 (s, 1H), 8.25 (s, 1H), 10.49 (s, 1H). MS (EI/CI) m/z: 475 [M+H].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[OH-].[K+].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[ClH:26].[Cl:26][C:24]1[CH:23]=[CH:22][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH2:17][N:11]([C:9](=[O:10])[CH2:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][CH2:34][C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:25]=1
Reactant: NCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=Cc1cccs1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CCNCc1cccs1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
A mixture of 3-amino-N-[2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]-oxazepin-10-yl)-2-oxoethyl]propanamide, monohydrochloride (2.00 grams) in methanol (160 mL) and potassium hydroxide (0.38 gram) was stirred at room temperature until a solution formed. To this was added a solution of thiophene-2-carboxaldehyde (0.62 gram) in methanol (20 mL), and the solution was stirred at room temperature under a nitrogen atmosphere for 4 hours. To the solution was then added sodium cyanoborohydride (0.46 gram), and the pH of the reaction was adjusted to approximately 6 with acetic acid. The reaction was stirred at room temperature under a nitrogen atmosphere for 48 hours, made acidic to pH 2 with 2N HCl, and evaporated in vacuo. The residue was suspended in water (150 mL), made basic to pH 11 with 1N NaOH, and extracted with chloroform (150 mL, and then 2×100 mL). The combined chloroform extracts were washed with 1N NaOH (2× 100 mL), water (100 mL) and brine (150 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 95:5 chloroform:ethanol (3A). The purified product was taken up in absolute ethanol (20 mL), cooled in an ice water bath, and acidified with 9.5M HCl in ethanol (1.5 mL). After several minutes, the solution was evaporated in vacuo, and the resulting foam was dried in vacuo at 56° C. The yield of the title compound was 0.79 gram (32%). Analysis calculated for C23H22ClN3O3S×1 HCl: C, 56.10; H, 4.71; N, 8.53; Cl, 14.40; S, 6.51. Found: C, 55.74; H, 4.72; N, 8.47; Cl, 14.51; S, 6.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[O:21][C:20]=23)[CH:23]=1
Reactant: CN(C)CCCN
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)NCCCN(C)C)c4)c3o2)cc(OC)c1OC
Yield: 33 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.062 mmol) and N,N-dimethyltrimethylendiamin (0.064 mmol) the product is prepared analogously to “A43” and obtained as yellow solid in a yield of 33%. HPLC (method A): Rt 2.45 min (purity 99.3%); LCMS (ESI+) (method E): Rt 1.56 min, M+H+ 490.3 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.82 (s, 1H), 8.77-8.68 (m, 1H), 8.60 (d, J=5.1, 1H), 8.27 (d, J=7.8, 1H), 8.01 (d, J=7.8, 1H), 7.78 (s, 1H), 7.77-7.69 (m, 2H), 7.37 (s, 2H), 3.93 (s, 6H), 3.74 (s, 3H), 3.49-3.18 (m, 2H), 2.45-2.10 (m, 8H), 1.78-1.63 (m, 2H).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15]C)[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([C:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[N:8]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:21][CH:22]=3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c(C3CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C3CCCC3)c3cc[nH]c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a solution of 4-(3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)benzenesulfonamide (22.4 mg) in acetonitrile (10 mL) were added sodium iodide (18.0 mg) and chloro(trimethyl)silane (52.1 mg), and the mixture was stirred at 80° C. for 5 hr. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)#[CH:16]>C(N(CC)CC)C.O.[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:14][C:11]1([C:16]#[C:15][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:9][CH2:10]1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: OC1(C#CC2(F)C=CC(c3ccccc3)=CC2)CN2CCC1CC2
Yield: 16.4 %

Procedure:
A mixture of 4-bromo-4'-fluorobiphenyl (1.0 g), 3-ethynyl-3-hydroxyquinuclidine (600 mg), bis(triphenylphosphine)-palladium (II) chloride (120 mg) and copper (I) iodide (60 mg) in dry triethylamine (15 ml) was stirred at reflux under an atmosphere of argon for 5 hours. The reaction mixture was cooled, diluted with water (60 ml), 2M aqueous sodium hydroxide solution added and extracted with dichloromethane. The mixed layers were filtered through diatomaceous earth and washed with dichloromethane. The organic layer in the filtrate was separated, dried (MgSO4) and evaporated to a residue which was further purified by flash column chromatography on alumina (ICN Alumina N 32-63) using a mixture of 10% ethanol in ethyl acetate as eluent to give a residue which was crystallised from a mixture of 10% ethanol in ethyl acetate to give 3-[2-(4-fluorobiphenyl-4-yl)ethynyl]quinuclidin-3-ol (210 mg) as a solid, m.p. 232°-233° C.; microanalysis, found: C, 78.0; H, 6.4; N, 4.5%; C21H20FNO.0.1H2O requires C,78.07; H,6.26; N, 4.34%; NMR (DMSO-d6): 1.2-1.4(1H, m), 1.5-1.7(1H, m), 1.8-2.01(3H, m), 2.6-2.8(4H, t), 2.8-3.15(2H, d of d), 5.6(1H, s), 7.22-7.4(2H, m), 7.45-7.55(2H, d) and 7.61-7.81(4H, m); m/z 322 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[C:7]([C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>ClCCl>[C:7]([C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[N:20]=[CH:19][C:18]([N:21]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:17][C:16]=1[CH3:22])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCN(C)C=O
Reactant: Cc1cc(N)cnc1Oc1cccc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1cnc(Oc2cccc(C(C)(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (350 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 0.5 hour, whereupon a pink-orange solution is obtained. To this solution, 6-(3-tert-butyl-phenoxy)-5-methyl-pyridin-3-ylamine (0.51 g) dissolved in 5.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 2 hours. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with ethyl acetate gives 0.56 g of the compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: OCCCCCCCCCCCBr
Reactant: COc1cc(CC#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
11.0 g (67 mmol) of [4-hydroxy-3-methoxy-phenyl]acetonitrile and 20.4 g (81 mmol) of 11-bromoundecan-1-ol were dissolved in 100 mL of N,N-dimethylformamide. 18.7 g (135 mmol) of potassium carbonate and 2.2.0 g (13 mmol) of potassium iodide were added and the suspension was heated to 80° C. After 48 h, the reaction mixture was cooled to room temperature and poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 16.6 g of {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile are obtained as a yellow solid (74% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:22]=[C:23]=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:8]([NH:22][C:23](=[O:24])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCN=C=O
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 91 %

Procedure:
Triethylamine (1.06 ml) and tetradecyl isocyanate (1.64 g) were added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (1.70 g) obtained in Example 3(4) in methylene chloride (17 ml). After being stirred for 18.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=60:1 to 30:1), thereby yielding the entitled compound (3.04 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[F:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:35]3[CH2:36][CH2:37][C@H:33]([F:32])[CH2:34]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: F[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CC[C@H](F)C3)ccc2n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 92 mg of (S)-(+)-3-fluoropyrrolidine hydrochloride are added, and the mixture is stirred at 40° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.[O:14]=[C:15]1[NH:24][CH:23]=[CH:22][C:21]2[N:20]=[C:19]([C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=3)[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:17][C:16]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O>CN(C=O)C.C(O)(=O)C.C(N(CC)CC)C>[OH:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[OH:12])[CH2:2][N:3]([CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:19]3[C:18]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:17][C:16]4[C:15](=[O:14])[NH:24][CH:23]=[CH:22][C:21]=4[N:20]=3)=[CH:32][CH:31]=1)[CH2:4][CH2:5]2
Reactant: Oc1cc2c(cc1O)CNCC2
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCc5cc(O)c(O)cc5C4)cc3)c(-c3ccccc3)cc12
Reaction time: 3 h

Procedure:
To 1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrobromide (46 mg) and 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (130 mg) in DMF (0.5 mL) was added, triethylamine (64 μL), this solution was stirred for 15 minutes then acetic acid (117 μL) was added and the solution stirred for 3 hours. Sodium triacetoxyborohydride (48 mg) in DMF (0.5 mL) was then added. The reaction mixture was stirred overnight, trifluoroacetic acid (100 μL) was added purified by HPLC to give 2-{4-[(6,7-dihydroxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl]phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one (1-13) as a yellow solid: 1H-NMR (500 MHz, d6 DMSO) δ 11.63 (s, 1H), 10.14 (bs, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 7.51 (m, 5H), 7.35 (m, 3H), 7.26 (m, 2H), 6.70 (d, 2H, J=7.3 Hz), 6.58 (s, 1H), 6.51 (s, 1H), 4.42 (m, 2H), 4.10 (m, 2H), 3.20 (m, 2H), 2.90 (m, 2H) MS m/z (M+11) 476.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)[C:21]1=O>C(O)C>[F:32][C:30]1[CH:31]=[C:26]([CH:22]2[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)[CH:27]=[C:28]([F:33])[CH:29]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1cc(F)cc(F)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(F)cc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (68 mg, 0.26 mmol) and of crude 2-bromo-6-(3,5-difluoro-phenyl)-cyclohexanone (78 mg, 0.27 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (40 mg, 34%) as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70 (s, 1H), 7.41 (s, 1H), 7.10 (d, 1H), 6.85 (s, 1H), 6.67-6.73 (m, 4H), 4.03 (m, 1H), 3.62 (s, 3H), 2.75 (m, 2H), 2.31 (s, 3H), 2.22 (m, 1H), 1.84 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH:15]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]=[CH:19][CH:18]=1)[CH3:16]>COCCOC>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:15]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[N:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(C(F)(F)F)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Trifluoromethylphenol (1.62 g) was added to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred at room temperature for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The mixture was stirred at room temperature for 24 hours. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the filtrate and the residue dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from hexane, to give 7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.1 g, (mp 100°-102° C.).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCc1ccc(N=Nc2ccc(OC)cc2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
All chemicals were obtained from Sigma-Aldrich Chemical Co. unless otherwise noted. One eq. of 4-butyl-4′-hydroxyazobenzene (obtained from Beam Corp.) and 1.1 eq. potassium carbonate were dissolved in acetone and degassed with argon. Iodomethane (2.5 eq) in acetone was degassed and added drop-wise to the stirred mixture. The mixture was heated to 45° C. and stirred overnight. The progress of the reaction was monitored by thin-layer chromatography (TLC); 12 h was usually sufficient for complete methylation. The hot reaction mixture was then filtered to remove the precipitated potassium iodide. The filtrate was collected and the solvent removed in vacuo. The solid residue was re-dissolved in chloroform and then insoluble salts were removed by filtration. The filtrate was washed with water, and the organic layer was separated and dried over magnesium sulfate. Removing the solvent in vacuo afforded a solid that contained the desired product (“BMAB”) containing a small amount of un-reacted starting material 4-butyl-4′-hydroxyazobenzene. Recrystallization from methanol at −68° C. afforded pure crystals of BMAB that were collected by filtration. (K 35 N 45 I) 1H NMR 200 MHz δ ppm=0.94 (t, 3H), 1.18 (q, 2H), 1.66 (q, 2H), 2.66 (t, 2H), 3.86 (s, 2H), 7.0 (d, 2H), 7.26 (d, 2H), 7.82 (d, 2H), 7.88 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.CC(O[N:16]=O)(C)C.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[CH3:9][N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[N:10]=[N:16]1
Reactant: CC(C)(C)ON=O
Reactant: CNc1nc(C)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc2nnn(C)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
6,N2-dimethyl-pyridine-2,3-diamine of Step A (1.5 g, 10.9 mmol), 2-methyl-2-nitrosooxy-propane (1.6 ml, 13.1 mmol), acetic acid (2.6 ml, 43.6 mmol), and ethanol (50 ml) were stirred at 60° C. for 60 min. After cooling to ambient temperature, sodium hydrogen carbonate (3 g) was added and the resulting mixture was stirred at ambient temperature for 20 min. The mixture was diluted with dichloromethane (20 ml), solids were filtered off, and the obtained solution was concentrated in vacuum. Chromatography on silica gel, eluting with dichloromethane-acetonitrile (93:7) yielded the title compound (1.23 g, 76%).