Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH2:55])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH:55][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (68 mg, LC/MS: m/z 745) was prepared from (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (70 mg) and (S)-2-Amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride using general procedure A.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[O:14][CH2:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[O:14][CH2:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCNCC2)C1

Procedure:
A solution of the product of Step H (405 mg, 0.83 mmol, 1 eq) and 5% Pd/C (100 mg) in ethanol (10 mL) at rt was placed under a balloon of hydrogen gas overnight. The suspension was filtered through celite, washed with methanol, and the filtrates concentrated to give the product of Step I as a gum. Calculated for C18H31N3O4: 354.2 (M+1). found: 354.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[F:10][C:11]([F:23])([F:22])[C:12](=O)[CH2:13][C:14]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=O>CC(O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][C:12]([C:11]([F:23])([F:10])[F:22])=[N:9]2)[N:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1cccc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(Cl)n2)n1
Yield: 89.7 %

Procedure:
To a stirred solution of 2-chloro-6-hydrazinopyridine (300 mg, 2.09 mmol) in 2-propanol (10.4 mL), was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.310 mL, 2.090 mmol) followed by 2 drops of conc HCl. The resulting mixture was heated to reflux overnight and then evaporated to dryness. A 2:1 mixture of regioisomeric products 45 (588 mg, 90% yield) were isolated as a pale yellow oil. LRMS (ESI): calc. 313.6; found 313.6 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:19].[Na+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(CSc1ccc(Cl)cc1)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(CS(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 40 °C

Procedure:
To a vigorously stirred solution of 199 g. (0.75 mole) of 4-chloro-2-(phenylthio)acetophenone in 2 liters of 1,2-dimethoxyethane (glyme) is added a solution of 175.5 g. (0.825 mole) of sodium periodate; the mixture is heated at 40°C for 7 days. The mixture is then filtered from the inorganic materials and the glyme distilled from the filtrate to give a slurry of crystals. These are filtered and this mixture of sulfoxide and starting material is separated from the inorganic contaminants by extraction into abs. ethanol. After filtration and concentration, the residue is dissolved in 1.5 liters of boiling hexane to give (after cooling and filtration) 91.8 g. of product, melting point 129°-130°C.
Reaction SMILES: [C-:1]#[N:2].[K+].S([O-])(O)=O.[Na+].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1>O.C(OCC)C>[OH:23][CH:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=1)[C:1]#[N:2]
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(-c2ccccc2C(O)C#N)cc1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of 6.0 g of potassium cyanide dissolved in 6 ml of water and a solution of 14 g of sodium hydrogensulfite dissolved in 35 ml of water were added dropwise at 0° to 5° C. to a solution of 8.00 g of 4'-methylbiphenyl-2-carbaldehyde (prepared as described in Preparation 1) dissolved in 10 ml of diethyl ether, and the resulting mixture was stirred at 5° to 10° C. for 3 hours and then at 20° C. for 30 minutes. At the end of this time, the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.7 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:36][C:37]([O:39]CC)=[O:38])=[O:5])[CH3:2].[OH-].[Na+].CCO>O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cn3)cc12
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(4-isopropoxyphenyl)-2-ethoxycarbonylmethyl-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid ethyl ester (260 mg, 0.46 mmol, see step (a) above), NaOH (aq, 1 M, 1.4 mL) and EtOH (2 mL) was stirred at 50° C. for 2.5 h, cooled, diluted with H2O (4 mL), washed with EtOAc and acidified to pH 5 with citric acid (aq, 1 M) and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated and purified by chromatography. Yield 144 mg (58%).
Reaction SMILES: CON(C)[C:4](=[O:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Br-].[Cl-].[Na+]>O1CCCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4](=[O:13])[CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: CON(C)C(=O)CCc1ccccn1
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(=O)CCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 169.9 %

Procedure:
While under a nitrogen atmosphere, a solution of N-methoxy-N-methyl-3-(pyridin-2-yl)propanamide (1.00 g, 5.15 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 16 mL, 8.0 mmol) in a dropwise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature for 3 h. The resulting solution was poured into saturated aqueous sodium chloride (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave 1-(pyridin-2-yl)hept-6-en-3-one as a colorless oil (828 mg, 85%). ESI MS found for C12H15NO m/z [190.1 (M+1)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
62.8 g of N-benzyloxycarbonyl glycine was dissolved in 1000 ml of tetrahydrofuran and the solution was cooled to -15° C., to which 42.3 g of isobutyl chloroformate and then 31.0 g of triethylamine were added dropwise at -15° to -5° C. and stirrd at -10° to -5° C. for 15 minutes. Next, 38.5 g of 4-piperidinecarboxamide was added while maintaining the temperature at -10° to -5° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The insoluble solid was filtered off. This solid was suspended in 500 ml of water, the suspension was stirred for 30 minutes and then the insoluble solid was filtered off. The wet solid was dissolved in 700 ml of ethanol with warming and the solution was concentrated to 200 ml at atmospheric pressure. After the concentrate was allowed to cool, 64.8 g of 1-(N-benzyloxycarbonylglycyl)-4-piperidinecarboxamide having the melting point of 164° to 166° C. was obtained. This was dissolved in 950 ml of methanol and 7 g of 5 % palladium on carbon was added thereto followed by subjecting to the catalytic hydrogenation while introducing hydrogen gas at room temperature. After 4 hours, the catalyst was filtered off and the reaction solution was concentrated to 100 ml. 250 ml of ethyl acetate was added and again the resultant solution was concentrated to 150 ml and allowed to cool so as to obtain the precipitate, which was filtered to obtain the titled compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([CH:16]=[CH:17][CH2:18][OH:19])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][CH:18]=[O:19])=[CH:20][CH:21]=1
Reactant: OCC=Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC=Cc1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (2.6 mL, 30 mmol) in methylene chloride was cooled to −70° C. in a dry ice/acetone bath and DMSO (4.2 mL, 60 mmol) was added slowly. After 10 minutes, a solution of 4-chlorocinnamyl alcohol (2.0 g, 12 mmol) from Step A in methylene chloride (12 mL) was added. The reaction was stirred at −70° C. for 80 min and then DIPEA (20 mL, 120 mmol) was added. After 5 min, the reaction was allowed to warm to rt over 2 h. The mixture was diluted with methylene chloride and washed with cold 2N hydrochloric acid (80 mL). The organic layer was washed with brine containing some aq. sodium bicarbonate, dried over sodium sulfate, and evaporated. The residue was purified by FC (0 to 10% ethyl acetate in hexanes) to give the title compound as a white solid. 1HNMR (CDCl3): δ 6.71 (dd, J=7.7 and 16.0 Hz, 1H), 7.450 (d, J=16 Hz, 1H), 7.43 and 7.52 (Abq, J=8.4 Hz, 4H), 9.72 (d, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:27][CH2:28][N:29]1[C:30](=[O:39])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]1=[O:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), 2-(2-bromo-ethyl)-isoindole-1,3-dione (229 mg) and potassium carbonate (125 mg), and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (83 mg, yield 55%).
Reaction SMILES: [CH2:1]([S:7][CH2:8][C:9](=[O:34])[C@@H:10]([NH:15][C:16](=[O:33])[CH2:17][CH2:18][C@H:19]([CH3:32])[CH2:20][NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[CH2:1]([S:7]([CH2:8][C:9](=[O:34])[C@@H:10]([NH:15][C:16](=[O:33])[CH2:17][CH2:18][C@H:19]([CH3:32])[CH2:20][NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:36])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCC[C@H](NC(=O)CC[C@H](C)CNC(=O)COc1ccccc1)C(=O)CSCc1ccco1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC[C@H](NC(=O)CC[C@H](C)CNC(=O)COc1ccccc1)C(=O)CS(=O)Cc1ccco1
Yield: 36.3 %

Procedure:
(s)-1-Furfurylthio-3-((s)-4-methyl-2-phenoxyacetylaminovalerylamino)-2-heptanone (176 mg) obtained in Example 3 was dissolved in methanol (10 ml) and water (10 ml). To the solution was added sodium metaperiodate (82 mg), and the mixture was reacted at room temperature for 48 hours. Then, methanol was removed in vacuo, saturated brine was added to the residue, and the resultant mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated and chromatographed on a silica gel column, eluting with hexane:ethyl acetate (1:1) to give the titled product (66 mg).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[ClH:15].C(N(CC)CC)C.[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43](=O)[NH:42][N:41]=2)=[CH:35][CH:34]=1>O>[ClH:15].[ClH:15].[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[N:41][N:42]=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 210 °C
Reaction time: 4 h

Procedure:
In the manner described in Example 45, a mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, 1.8 ml (12.74 mmol) 4-isopropylaniline, and 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone is stirred for 4 h at 210° C. The frozen melt is then suspended in water using an ultrasonic bath, filtered, and the filtrate evaporated in the RE. The oil-like residue is distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue is then stirred with acetonitrile, filtered off from some non-transformed 4-(4-pyridylmethyl)-1(2H)-phthalazinone, and the filtrate evaporated under vacuum. Flash chromatography of the residue on silica gel with a particle size of 0.04-0.06 mm using acetate/methanol mixtures (20:1 and 10:1) yields a resin (free base of the title compound), which is dissolved in a mixture of 4 ml methanol and 1.5 ml of 3 N methanolic HCl. After evaporation under vacuum, recrystallization of the residue from methanol/ether, drying under HV (8 h, 120° C.), and equilibration for 16 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 9.4%; m.p. >250° C.; ESI-MS: (M+H)+=355.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH3:18][C:19]([CH3:25])([CH2:22][CH2:23][CH3:24])[CH2:20][OH:21].[H-].[Na+]>>[CH3:18][C:19]([CH3:25])([CH2:22][CH2:23][CH3:24])[CH2:20][O:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1
Reactant: CCCC(C)(C)CO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) and 2,2-dimethylpentanol (3.8 mL) at 50° C. was added sodium hydride (396 mg, 60% dispersion) in portions. To the resultant viscous foam was added a further portion of 2,2-dimethylpentanol (1.5 mL). The reaction was stirred at 50° C. for 72 h. The reaction mixture was cooled then carefully quenched with water (10 mL) and extracted with EtOAc (3×25 mL). The organics were combined, washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. This was azeotroped with toluene (×3) and the resulting viscous yellow oil was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (30-80%) to afford the title compound as a brown solid (372 mg).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>CC(C)=O>[Br:9][CH2:10][CH2:11][CH2:12][C:13]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:14]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)CCCBr
Solvent: CC(C)=O
Product: O=C(CCCBr)Nc1ccc(O)cc1
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A mixture of 30.9 g (0.28 mol) of p-aminophenol in about 300 mL of acetone was stirred in an ice bath and a solution of 25 g (0.14 mol) of 4-bromobutyryl chloride in about 50 mL of acetone was dripped in over 20 minutes. The reaction was stirred cold for another 1/2 hour and then at room temperature for two hours. It was then ice cooled and the mixture filtered. The precipitate was washed with about 200 mL of cold acetone. The filtrate was evaporated and the residue slurried in about 200 mL of 1N HCl, whereupon a precipitate formed. The mixture was ice cooled, filtered, and the precipitate was washed with additional 1N HCl followed by water. The precipitate was dissolved in about 100 mL of ethanol at room temperature, diluted with about 160 mL of water, ice cooled and filtered. The precipitate was washed with a mixture of water and ethanol and then with hexane to yield 18.1 g (52%) of 4-bromo-N-(4-hydroxyphenyl)butanamide, mp 142.5°-144.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[C:28]([C:29]([C:31]5([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:31]1([C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)[N:21]=3)[NH:26][CH:27]=2)=[O:30])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(N5CCNCC5)cc4)nc23)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A solution of 4-{4-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (35 mg, 0.069 mmol) in DCM (5 ml), at 0° C., was treated with TFA (0.15 ml, 2.01 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then refluxed for 1.5 hours. The reaction mixture was concentrated to dryness, and the resulting residue was partitioned between sat. NaHCO3 and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated providing 25 mg (89%) of (1-methyl-cyclohexyl)-[2-(4-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a yellow solid. MP 214-216° C., M+H=404.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[CH:11]=[N:10]1.[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[CH:11][C:12]=3[CH:25]([CH3:27])[CH3:26])=[CH:17][C:18]=2[CH3:24])[CH3:23])=[CH:34][CH:33]=1
Reactant: CNc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(CN(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
To an ambient temperature solution of {4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amine (82 mg, 0.204 mmol) in acetonitrile (3 mL) are added (4-bromomethyl-phenyl)-acetic acid methyl ester (52 mg, 0.214 mmol) and cesium carbonate (133 mg, 0.408 mmol). The reaction mixture is heated to 80° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue is chromatographed (SiO2 40 g, 0% to 20% EtOAc/Hex). Reversed phase HPLC (C18 OBD 19×100 mm, 30 to 70% ACN/water (0.1% TFA) at 20 mL/min) is employed to remove approximately 10% starting amine present to yield the title compound (78 mg, 68%). LC-ES/MS m/e 566.3 (M+1), 95%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccc(/C=C/c2ccccc2)c1
Yield: 65.1 %

Procedure:
A mixture of (E)-3-nitrostilbene (3.63 g), hydrochloric acid (35%, 10 ml) and iron powder (3.6 g) in ethanol (30 ml) was refluxed for 1 hour. The mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give (E)-3-aminostilbene (2.05 g).