Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][C:33]5[CH:34]=C(C=CC=5)C(OC)=O)[C:28](=[O:43])C4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.N1(C2N=CC(NC(C3OC(N4CCCC(C)C4)=NC=3C(F)(F)F)=O)=CC=2)CCCNCC1.ClC([O:79][CH:80]1[CH2:84][CH2:83][CH2:82][CH2:81]1)=O>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:34][CH2:33][CH2:32][N:29]([C:28]([O:79][CH:80]5[CH2:84][CH2:83][CH2:82][CH2:81]5)=[O:43])[CH2:30][CH2:31]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Reactant: O=C(Cl)OC1CCCC1
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCNCC4)nc3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCN(C(=O)OC5CCCC5)CC4)nc3)o2)C1

Procedure:
Compound 43 was prepared by the general procedure for compound 8, by using compound 39 and cyclopentyl chloroformate as starting materials. 1H NMR (500 MHz, CDCl3) δ 8.10 (br s, 1H), 7.90 (d, 1H, J=9 Hz), 7.50 (s, 1H), 6.50 (d, 1H, J=9 Hz), 5.10 (br s, 1H), 4.10 (t, 2H, J=14.5 Hz), 3.80 (m, 2H), 3.60 (m, 3H), 3.40 (t, 1H, J=6 Hz), 3.25 (t, 1H, J=6 Hz), 3.05 (t, 1H, J=13 Hz), 2.70 (t, 1H, J=13 Hz), 1.55-2.00 (m, 16H), 1.20 (q, 1H, J=12.5 Hz), 1.00 (d, 3H, J=7 Hz). MS (M+1): 565.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.S(=O)(=O)(O)O>C(O)CCCCCCC>[CH2:5]([O:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1)[CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:10][CH3:9]
Reactant: Oc1ccc(O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCCCCCCCO
Product: CCCCCCCCOc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
216 g of naphthohydroquinone and 527 g of n-octyl alcohol were placed in a 2 l three-necked flask, and 114 ml of concentrated sulfuric acid was dropwisely added thereto for 30 minutes under nitrogen gas stream while stirring. Thereafter, the reaction mixture was heated at 50° C. for 1 hour and then cooled to room temperature. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with ammonia-water until the washing reached pH of 5 to 6. The ethyl acetate layer was further washed two times with an aqueous sodium chloride solution and, then, dried with anhydrous sodium sulfate. The dried ethyl acetate solution was concentrated under reduced pressure to precipitate crystals. The crystals were filtered off, and the filtrate was further concentrated under reduced pressure to distill off ethyl acetate and n-octyl alcohol to obtain oily substance. The oily substance was purified by column chromatography using a mixed solvent of n-hexane and ethyl acetate and, then, recrystallized from n-hexane to obtain 190 g of white crystals having a melting point of 73° to 74° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C@@H:39]([OH:41])[CH3:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[C@@H:39]([OH:41])[CH3:40])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](O)c1nc2ccccc2[nH]1
Reactant: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 140 °C
Yield: 54 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol), (S)-1-(1H-benzoimidazol-2-yl)ethanol (84 mg, 0.52 mmol), tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol), XPhos (82 mg, 0.17 mmol) and Cs2CO3 (279 mg, 0.86 mmol) in toluene (3 mL) was purged with argon then heated at 140° C. for 1 h in a microwave reactor. Further tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol) and XPhos (82 mg, 0.17 mmol) were added and the mixture heated at 140° C. for a further 1 h. The reaction mixture was filtered through Celite®, washing with EtOAc and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording the title compound (127 mg, 55%). LCMS (method A): RT 3.27 min [M+H]+ 547.4
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc(Br)cc2)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(-c2ccc(Br)cc2)cnc1Cl
Temperature: 120 °C

Procedure:
A mixture of 10.2 g of 5-(4-bromphenyl)-2-hydroxy-3-nitropyridine (starting material H4) and 40 ml of phosphorous oxychloride is heated under reflux to 120° C. for 3 hours. After cooling the mixture is carefully added to ice/water, then neutralized with sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (ethyl acetate/petroleum ether 1:12). Concentration of the chromatographically pure fractions gives 1.52 g of the title compound as yellow crystals of m.p. 116–117° C. The mass spectrum shows the molecular peak M+ at 314 Da.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:14](N)=[O:15])[NH:10][C:11](N)=[O:12]>CN1CCCC1=O>[CH2:1]([N:8]1[C:11](=[O:12])[NH:10][NH:9][C:14]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)NNC(N)=O
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1Cc1ccccc1

Procedure:
53.5 g of benzylamine and 59 g of hydrazodicarboxamide in 100 ml of N-methylpyrrolidone are stirred at 175° C. for 4 hours and at 200° C. for 5 hours. The solvent is then distilled off in vacuo, the residue is triturated with 50 ml of 10% strength sodium hydroxide solution, and the resulting residue is filtered off. The filtrate is neutralised with 10% strength hydrochloric acid. A precipitate is thereby formed and is filtered off and washed with water. 67 g (70% of the theoretical yield) of 4-benzyl-1,2,4-triazolidine-3,5-dione are obtained as colourless cyrstals of melting point 185°-188° C. (CH3CN).
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:22]>[Ni].C1COCC1>[NH2:19][C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([F:22])[C:2]=1[Cl:1])[CH2:6][NH:7][C:8]([C:10]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:12]1)=[O:9]
Reactant: O=C(NCc1cc(F)c(Cl)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)cc(F)c1Cl

Procedure:
H2 was passed through a shaken mixture of N-(4-chloro-3-fluoro-5-nitrobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide (980 mg, 2.88 mmol), Ra—Ni (17 mg, 0.29 mmol) and THF (50 mL) at rt for 1.5 h. The mixture was filtered through celite and concentrated.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:21]([NH2:24])[CH:22]=[CH2:23].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:21]([NH:24][S:17]([C:13]1[S:14][C:15]([Br:16])=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])[CH:12]=1)(=[O:19])=[O:18])[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)c(Br)s1

Procedure:
4-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonylchloride, prepared as in Step III of Example 23 (100 mg; 0.229 mmol; 1 eq) is dissolved in DCM (10 ml). Allyl amine (0.15 ml; 1.14 mmol; 5 eq) and DIEA (0.17 ml; 0.70 mmol; 3 eq) are added under a nitrogen atmosphere. After 2 hours reaction, solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is purified by reverse preparative HPLC, affording N-(5-{5-[(allylamino)sulfonyl]-2-bromo-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide as a white solid (35 mg; 35%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][N:18]([CH:35]([CH3:37])[CH3:36])[C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=2)[CH2:15][N:14]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])(C)(C)C.Cl>O1CCOCC1>[CH2:38]([N:14]1[CH2:13][C@@H:12]([CH2:11][NH:7][CH:8]([CH3:10])[CH3:9])[C@@H:16]([CH2:17][N:18]([CH:35]([CH3:37])[CH3:36])[C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=2)[CH2:15]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CN(C(=O)OC(C)(C)C)C(C)C)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(3S*,4R*)-1-benzyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidin-3-ylmethyl]-isopropyl-carbamic acid tert-butyl ester (0.41 g, 0.66 mmol), is added a dioxane solution of HCl 4N (10 mL). The reaction mixture is stirred for 2 h at room temperature. The solvent is concentrated and water (20 mL), an aqueous solution of NaOH 4N (5 mL) and Et2O (25 mL) are added. The layers are separated and the aqueous one extracted twice with Et2O. The combined organic extracts are dried (MgSO4), and the solvent is removed in vacuo to give the title compound which is used without further purification in the next step. MS (LC-MS): 526.4 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.53 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.78 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:16]([C:11]1([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([CH:6]=2)[OH:9])[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC1(c2cc(OC)cc(OC)c2)CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCC1(c2cc(O)cc(O)c2)CCCC1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 1-(3,5-dimethoxyphenyl)-1-hexyl-cyclopentane (1 equiv.) in dry methylene chloride (0.04M) at −78° C. under an argon atmosphere was added boron tribromide (2.5 equiv., 1M solution in methylene chloride). Following the addition, the reaction temperature was gradually raised over a period of 3 h to −20° C. Stirring was continued at that temperature until completion of the reaction. Unreacted boron tribromide was destroyed by addition of methanol and ice at 0° C. The resulting mixture was warmed at room temperature, stirred for 40 min and the solvent was removed in vacuo. The residual oil was diluted with ethyl acetate and the solution was washed with saturated sodium bicarbonate, water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (40% diethyl ether-petroleum ether as eluent) afforded the title compound in 90% yield.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].S(=O)(=O)(O)[O-].[K+]>CS(C)=O.ClCCl>[CH:9]([CH:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:8]
Reactant: CC(C)C(CO)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)C(C=O)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.97 ml of triethylamine are added dropwise at 0° C. to the solution of 3.0 g of tert-butyl 4-(2-hydroxymethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate in 11 ml of dimethyl sulphoxide and 55 ml of dichloromethane. 5.23 g of sulphur trioxide-pyridine complex are added in 3 portions at intervals of 10 minutes and the reaction mixture is stirred at 0° C. for a further 3 hours. The reaction mixture is poured onto ice-water, adjusted to pH=2.5 with saturated aqueous potassium bisulphate solution and extracted with diethyl ether (3×)—the combined organic phases are washed successively with water and 5% aqueous sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue as a yellow oil. Rf=0.46 (1:2 EtOAc-heptane).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:14])[NH:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:14])[C:5]([CH:2]([NH:1][C:20]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:21])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(C2CC2)[nH]c1=O
Product: CCC(NC(=O)C1CCCC1)c1nnc(C2CC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 250 mg (1.29 mmol) 6-(1-aminopropyl)-3-cyclopropyl-1,2,4-triazin-5(4H)-one, 170 mg (1.29 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:18])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:18])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[OH:8]
Reactant: CN(CC(=O)c1cccc([N+](=O)[O-])c1)Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanone (28 g, 1.00 equiv, Crude) in methanol (280 mL), NaBH4 (6.38 mg, 0.17 mmol, 2.00 equiv). The resulting solution was stirred for 0.5 h at 0° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of acetone. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5). This resulted in 14 g of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanol as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([C:8](=[O:12])[CH2:9][CH2:10]Cl)[CH:5]=[CH:6][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-]>CC(=O)OCC>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:5]([CH2:10][CH2:9][C:8]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(CCCl)c1cccc(Br)c1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(Br)c(F)c21
Temperature: 180 °C
Reaction time: 2 h

Procedure:
1-(3-Bromo-2-fluorophenyl)-3-chloropropan-1-one (3.3 g) was added to a slurry of AlCl3 (16.6 g) and NaCl (4.3 g) at 130° C. The resulting mixture was stirred at 180° C. for 2 hours. The reaction was cooled to r.t. and the residue was dissolved in EA (200 mL). The solution was washed with water (300 mL) and brine (50 mL) and finally dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: EA/PE 1:10) to provide the subtitle compound. MS ESI+: m/z=229 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Oc3ccc(S(C)(=O)=O)cc3)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Oc3ccc(S(C)(=O)=O)cc3)cc2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 1.6 g (3.9 mmol) of 2-propionyl-3-hydroxy-5-(4-(4-(methylsulfonyl)phenoxy)phenyl)-cyclohex-2-en-1-one in 10 mL of methylene chloride and 10 mL of absolute ethanol, at room temperature was treated with 0.50 g (5.2 mmol)of ethoxyamine hydrochloride and 0.40 g (4.9 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted twice with 20 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel. Evaporation of the solvent left the product as a solid residue which was recrystallized from a mixture of diethyl ether and methylene chloride to yield 1.5 g (84 percent of theoretical) the above named product as a white solid melting at 155°-157° C. 1H NMR (CDCl3): δ1.10-1.48 (m, 6H, both --CH2CH3 's), 2.57-3.62 (m includes s at 3.03 for CH3SO2 --, 10H), 4.12 (q, J=7 Hz, 2H, --OCH2), 6.95-7.45 (m, 6H, aromatics), 7.90 (d, J=7 Hz, 2H, aromatics), 15.0 (very broad s, enol H) (Compound 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[CH:23]=[CH:22][C:12]([CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:28][N:27]=[C:7]([C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)c2ccc(OC)cc2)cc1)OCC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(C(=NO)c2ccc(OC)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Diethyl 4-(4-methoxybenzoyl)benzylphosphonate, 32-d, (500 mg, 1.38 mmol) was dissolved in 95% EtOH (5 ml). Hydroxylamine hydrochloride (288 mg, 4.14 mmol) and Na2CO3 (439 mg, 4.14 mmol) was added to the solution. The reaction mixture was then stirred for 10 h under reflux. The resulting mixture was cooled to ambient temperature, filtered. The filtrate was concentrated under reduce pressure, extracted with ethyl acetate/H2O (3×10 ml). The organic layer was combined and washed with brine (2×10 ml) dried over Na2SO4 anhydrous, concentrated under reduce pressure to dry. The pure product, 32-e, was obtained as colorless oil (460 mg, 88% yield). 1H NMR (300 MHz, CDCl3) δ 0.67-0.85 (m, 6H), 2.628-3.306 (m, 2H), 3.30-3.35 (d, J=46.8, 3H), 3.51-3.63 (m, 4H), 6.31-6.33 (m, 1H), 6.44-6.47 (m, 1H), 6.74-6.92 (m, 6H). LC-MS 378 [MH]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[CH:21][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccc2ccccc2c1
Product: COc1ccc2c(-c3ccc4ccccc4c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and naphthalene-2-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-naphthalen-2-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 381(MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.C(OC([N:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39](Br)=[C:34]2[CH:33]=[CH:32]1)=O)(C)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1>[NH:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)=[C:34]2[CH:33]=[CH:32]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris(dibezylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (ESI): m/z 379.2 [M+1]+.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)O1.[H-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:6]3[C:5]4[C:25](=[CH:24][CH:28]=[CH:15][CH:4]=4)[CH2:26][C:2]=3[C:7]=2[C:8]#[N:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c(=O)o2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c3c2-c2ccccc2C3)cc1

Procedure:
A mixture of 2-oxo-4-(pyrrolidin-1-yl)-6-p-tolyl-2H-pyran-3-carbonitrile (280 mg), indanone-2 (132 mg) and NaH (39 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 182-184° C.; ESMS 351 (M++1); IR (KBr) 2205 cm−1 (CN); 1H NMR (200 MHz, CDCl3) δ 1.99-2.06 (m, 4H, 2CH2), 2.48 (s, 3H, CH3), 3.63-3.72 (m, 4H, 2CH2) δ 4.03 (s, 2H, CH2), 6.45 (s, 1H, ArH), 6.80 (d, J=7.6 Hz, 1H, ArH), 7.03-7.18 (m, 2H, ArH), 7.27-7.36 (m, 4H, ArH), 7.47 (d, J=7.0 Hz, 1H, ArH).