Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[Cl:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cc(Cl)ccc1Cl
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 15.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (750 mg, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.6 g, 0.02 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.5 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 15%) as yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])CCC.[F-].[K+]>CN(C)C=O.O>[O:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC[Sn](/C=C/C(=O)OCC)(CCCC)CCCC
Reactant: Brc1ccc(OCc2ccccc2Oc2ccccc2)cn1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2Oc2ccccc2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-((2-phenoxybenzyl)oxy)pyridine (1.0 g) in dimethylformamide (7 ml), 1.26 g of ethyl (2E)-3-(tributylstannyl)acrylate and 350 mg of tetrakis triphenylphosphine palladium were added, and the reaction solution was stirred overnight at 100° C. under nitrogen atmosphere. The reaction solution was cooled, then 15 ml of a saturated aqueous potassium fluoride solution was added, and the reaction solution was stirred for 1 hour, followed by removing insoluble matters by filtration through Celite and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water, extracted with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-25:75-30:70)) to afford the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:3]1[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(=O)N(C)OC)c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(=O)N(C)OC)c1=O
Yield: 69 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (500 mg, 1.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (295 mg, 1.42 mmol), Na2CO3 (302 mg, 2.85 mmol) and Pd(PPh3)4 (74.5 mg, 0.0645 mmol) in DME (11.4 mL) and water (2.9 mL) was heated to reflux for 15 h under Ar. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography on basic silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title compound (345 mg, 69% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.25 (3H, s), 3.59 (3H, s), 3.80 (3H, s), 3.90 (3H, s), 7.35-7.44 (1H, m), 7.50-7.59 (1H, m), 7.84-7.94 (1H, m), 7.97 (1H, s), 8.23 (1H, d, J=2.5 Hz), 8.58 (1H, s).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([CH2:33][NH:34][CH2:35]C(OC(C)(C)C)=O)[S:30][CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([CH2:33][NH:34][CH3:35])[S:30][CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2csc(CNCC(=O)OC(C)(C)C)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OC)cc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
2.9 g (5 mmol) of methyl 2(S)-(2-benzoylphenylamino)-3-(4-{5-[(tert-butoxycarbonylmethylamino)methyl]thiophen-3-yl}phenyl)propanoate are placed in 30 ml of dichloromethane and 2.5 ml (32 mmol) of trifluoroacetic acid. After stirring at room temperature for 18 hours, the reaction medium is evaporated to dryness. 2.4 g (100%) of methyl 2(S)-(2-benzoylphenylamino)-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](F)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O-:13].[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of 3,5-difluoro-benzoic acid (6.38 g, 40.3 mmol) in DMF (10 mL), NaOMe (6.48 g, 121 mmol) was added at room temperature. The mixture was stirred at 120° C. for 12 h, cooled to room temperature and filtered. The solid obtained was dissolved in H2O and pH was adjusted to 3˜4 with 4M aqueous HCl solution. The mixture was filtered again and the white solid was washed with water (3×10 mL) to give 5.1 g of 3-fluoro-5-methoxybenzoic acid. 1H NMR (CDCl3): δ 7.37-7.43 (m, 2H), 6.83-6.88 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: C(O[K])(C)(C)C.[C:7](=[O:14])([O:11][CH2:12][CH3:13])OCC.C1(C)C=CC=CC=1.[C:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])[CH3:23]>O>[CH2:12]([O:11][C:7](=[O:14])[CH2:23][C:22](=[O:24])[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:13]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 71.1 g (0.63 mol) portion of tert-butoxy potassium was added to 194.7 g (1.65 mol) of diethyl carbonate at 60 to 65° C. and stirred at 60 to 65° C. for 1 hour, and then 180 ml of toluene solution containing 50 g (0.40 mol) of 2-acetylthiophene was added dropwise thereto at 75 to 80° C. and stirred at 75 to 80° C. for 2 hours. The reaction solution was cooled down to room temperature, mixed with 725 g of water, extracted with 600 ml of ethyl acetate, washed with saturated brine, concentrated and then distilled under a reduced pressure to obtain 65.2 g of 3-oxo-3-(2-thienyl)propionic acid ethyl ester (yield 83%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:13](=[O:14])[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27](Cl)[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19]>CN(C)C=O.C(Cl)Cl>[NH2:3][C:4]1[C:5]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([CH:27]([C:22]3[CH:21]=[C:20]([Cl:30])[C:17]([C:18]#[N:19])=[C:16]([Br:15])[C:23]=3[O:24][CH2:25][CH3:26])[CH3:28])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (36 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and was stirred for 10 minutes. 2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (Example 43, step 4) (60 mg, 0.2 mmol in N,N-dimethylformamide (2 mL) was added and the reaction was stirred at 50° C. overnight. The mixture was diluted with methylene chloride, washed with sat'd NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by FCC eluting with CH2Cl2/MeOH (0-10%), to give 4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (0.04 g, 50%) as a solid, LCMS calculated for C18H15BrClN5O2 (M+H)+: m/z=450.0, 448.0; found: 450.0, 448.0.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.O=[C:12]1[C:17]([CH2:18][CH2:19][C:20]([O:22]CC)=O)=[CH:16][CH2:15][CH2:14][CH2:13]1.Cl>C1COCC1.CCOCC>[O:22]1[CH:12]2[C:17](=[CH:16][CH2:15][CH2:14][CH2:13]2)[CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)CCC1=CCCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=C2CCCOC2CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 48 mL diisobutylaluminum hydride (1.0 M in cyclohexane) was cooled to −78° C. and a solution of 2.335 g ethyl 3-(6-oxocyclohex-1-en-1-yl)propanoate in 48 mL THF was added. The reaction was warmed to 0° C. and stirred for one hour, then warmed to RT and stirred for one more hour. The reaction was not complete at this point, so 10 mL additional diisobutylaluminum hydride solution was added the reaction was and stirred at RT for two hours. The reaction was then cooled to −78° C. and then 25 mL 6 M HCl was added dropwise. After the addition was complete, the reaction was allowed to return to RT and was stirred overnight. The reaction was diluted with 200 mL Et2O then washed 2× with water, then with brine. The organic layer was dried over Na2SO4 then filtered, concentrated, and purified on silica gel to provide the title compound.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:15]=[CH:14][N:13]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:12]2=[O:35]>C1COCC1.CO>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:3])[CH2:25][CH2:26]1)[N:15]=[CH:14][N:13]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:12]2=[O:35]
Reactant: [BH3-]C#N
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A 37% aqueous solution of formaldehyde (501 μl, 6 mmol) followed by sodium cyanoborohydride (228 mg, 3.6 mmol) were added in portions to a solution of 6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.21 g, 3 mmol) in a mixture of THF/methanol (10 ml/10 ml). After stirring for 30 minutes at ambient temperature, the organic solvents were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.02 g, 82%).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12](=[O:13])[N:11]([C:14]2[S:15][C:16]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:19])[N:18]=2)[CH:10]=[N:9]1)(=O)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CO>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:6][CH2:7][N:8]2[C:12](=[O:13])[N:11]([C:14]3[S:15][C:16]([C:20]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:29])=[C:17]([CH3:19])[N:18]=3)[CH:10]=[N:9]2)=[CH:33][CH:32]=1
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: Cc1nc(-n2cnn(CCNCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 66 %

Procedure:
A solution of 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate (0.10 g, 0.23 mmol) and (4-fluorophenyl)methanamine (0.09 g, 0.69 mmol) in anhydrous methanol (5 mL) was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 66% yield (0.07 g): mp 106-107° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.59 (br s, 1H), 8.56-8.47 (m, 1H), 8.25 (s, 1H), 7.73-7.65 (m, 1H), 7.32-7.18 (m, 3H), 7.00-6.89 (m, 2H), 6.44 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.98 (t, J=5.8 Hz, 2H), 3.77 (s, 2H), 3.00 (t, J=5.8 Hz, 2H), 2.64 (s, 3H): MS (ES+) m/z 468.2 (M+1).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)(=O)=O)=CC=1.[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:28][C@@:26]1([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[C:59]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=2)[CH:58]=1)[OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[O:28][C@@:26]1([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[C:59]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[CH:67][CH:66]=2)[CH:58]=1)[OH:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reactant: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(OC2CCOC2)cc1

Procedure:
0.10 g tetrahydrofuran-3-yl toluene-4-sulphonate are added to a mixture of 0.24 g 1-(2,3,4,6-tetra-O-benzyl-(β-D-glucopyranos-1-yl)-3-(4-hydroxy-benzyl)-4-methyl-benzene and 0.13 g caesium carbonate in 2.5 ml of dimethylformamide. The mixture is stirred for 4 h at 65° C., before water is added. It is extracted three times with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is removed. The residue is purified through silica gel purified (cyclohexane/ethyl acetate 10:1->4:1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][CH:5]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([N:6]1[CH:5]=[C:4]([Br:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Br)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.656 g, 16.4 mmol) was carefully added to a solution of 4-bromoisoquinolin-1(2H)-one (3.5 g, 15.6 mmol) in anhydrous DMF (60 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 min, then benzyl bromide (8.02 g, 46.9 mmol) was added slowly. The reaction was allowed to warm to rt and stirred for 17 h. After that time the reaction was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 2-benzyl-4-bromoisoquinolin-1(2H)-one (4.55 g, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=7.4 Hz, 1H), 7.79-7.84 (m, 1H), 7.71-7.79 (m, 1H), 7.53-7.60 (m, 1H), 7.29-7.38 (m, 6H), 5.21 (s, 2H); ESI MS m/z 314 [M+H]+ and 316 [M+H]+.
Reaction SMILES: C[O-].[Na+].[CH3:4][Si:5]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)([CH3:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N:26](OCCC(C)C)=[O:27].C(O)(=O)C>CO>[CH3:4][Si:5]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[N:26][OH:27])[C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1)([CH3:13])[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: CC(C)CCON=O
Reactant: CC(=O)Cc1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)C(=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
28 ml of a 30% solution of sodium methanolate in methanol are added at room temperature to 31.6 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propan-2-one in 300 ml of methanol, and 27 ml of isopentyl nitrite are then added dropwise. The reaction mixture is stirred for a further hour and rendered neutral with acetic acid; the solvent is evaporated off in vacuo. 200 ml of ethyl acetate are added to the residue; the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off in vacuo. Recrystallisation from diethyl ether/hexane yields the title product having a melting point of 115-117° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni].CO.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
In the presence of 30 mg of Raney nickel, 110 mg (0.30 mmol) of 3-(3-nitro-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine are hydrogenated in 3 ml of methanol and 3 ml of THF. The catalyst is filtered off, then 15 g of silica gel are added to the filtrate, which is then concentrated by evaporation. Application of the powder to a silica gel column, elution with methylene chloride/ethanol (15:1) and stirring of the crude product with diethyl ether/hexane yield 3-(3-amino-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine; m.p. 264-266° C.; TLC: Rf =0.45 (methylene chloride/methanol 10:1); HPLC: TRet (Grad20-100)=9.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:29]([CH3:30])=[N:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:29]([CH3:30])=[N:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Br)cc(CO)c21
Reactant: COC(=O)c1cnc2[nH]nc(C)c2c1
Product: COC(=O)c1cnc2c(c1)c(C)nn2Cc1cc(Br)cc2cnn(CC(C)C)c12
Yield: 50 %

Procedure:
Compound 38 was prepared following general method 3A, using compound 18 as a starting material and 3-Methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester as the heterocycle. Yield: 50%.
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[N:19](C(OC(C)(C)C)=O)[C:18]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:14])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([CH2:10][CH2:11][O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:14])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCC(=O)OCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)OCCCC(=O)c1ccccc1
Reaction time: 3.5 h
Yield: 82.6 %

Procedure:
Dissolve 3-[(phenacyl)carbethoxymethyl-amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.4 g, 0.71 mmol) in methylene chloride (6 mL) and add, by dropwise addition, trifluoroacetic acid (6 mL). Stir for 3.5 hours and pour slowly into saturated sodium hydrogen carbonate (100 mL). Extract with ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize the residue (ethyl acetate/hexane) to give the title compound (0.28 g, 85%); mp 139°-40° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[O:13]1CCOCC1>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2
Reactant: C1COCCO1
Reactant: Cc1ccc2cccc(O)c2n1
Product: O=Cc1ccc2cccc(O)c2n1
Temperature: 80 °C
Yield: 38 %

Procedure:
A solution of 8-hydroxy-2-methylquinoline (6.0 g, 37.7 mmol) in dioxane (15 ml) was added to a stirred solution of SeO2 (6.3 g, 56.8 mmol) in dioxane (80 ml) dropwise at 50° C. and the mixture was heated up to 80° C. for further 20 h. The resulting mixture was filtered. The filtrate was concentrated and the residue purified by column chromatography with Hex/EA=(15:1 to 10:1) to give 8-hydroxyquinoline-2-carboxaldehyde (2.45 g, 38%) derivatives as intermediates. Intermediate was converted into N-substituted compounds by reductive amination with aminoalcohol, aminoalkyne or other heterocycles to give series of compounds. 8-alkoxy-2-methyl quinoline were oxidized to give 8-alkoxyquinoline-2-carboxaldehyde derivatives and followed by the same method to give compounds M to O.