Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1)=[O:5]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)c1ccccc1
Yield: 49.6 %

Procedure:
2-Methyl-2-phenylpropionic acid (33 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (23 mg, yield 50%) was obtained as slightly brown powder in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH2:14])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1.[H-].[Na+].C(N(CC)C(C)C)(C)C.[OH:26][C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH:14][C:33]([N:30]3[CH2:29][CH2:28][C:27]([OH:26])([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=4)[CH2:32][CH2:31]3)=[O:34])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1
Reactant: O=C(Cl)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Reactant: COc1nc(SC)nc2sc(N)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1nc(SC)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
A magnetically stirred mixture of 7-Methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-ylamine (500 mg, 2.19 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at 25° C. was treated with sodium hydride (60% suspension in mineral oil, 265 mg, 6.58 mmol). The reaction mixture was stirred at 50° C. for 1 h. At this time, the reaction was cooled to room temperature and was treated with N,N-diisopropylethylamine (850 mg, 6.58 mmol) and 4-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidine-1-carbonyl chloride (810 mg, 2.63 mmol). The reaction mixture was stirred at room temperature for 3 d. At this time, the reaction was concentrated in vacuo, poured into water and extracted with ethyl acetate. The organics were washed with a 2N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98:2 methylene chloride/methanol) afforded 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-yl)-amide (375 mg, 34%) as a red solid. LRMS for C20H20F3N5O3S2 (M+H)+ at m/z=499. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)([O-])=O.[H][H]>CO.[Pd]>[CH:14]1[C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCOCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCOCC2

Procedure:
2-Nitro-5,6,8,9-tetrahydro-7-oxa-benzocycloheptene (270 mg/1.3 mmol) was dissolved in anhydrous methanol (ca. 10 mL) and the solution added to a Parr flask. Palladium (10% on charcoal) was added carefully and the mixture shaken under 40 psi of hydrogen for 2 hours. The mixture was then filtered and the colorless filtrate concentrated onto celite. Chromatography on an amine-bonded column (eluting with 0→60% ethyl acetate/hexanes) afforded 5,6,8,9-tetrahydro-7-oxa-benzocyclohepten-2-ylamine as a colorless solid (200 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J=7.6 Hz, 1H), 6.42 (m, 2H), 3.78 (m, 4H), 3.55 (br s, 2H), 2.88 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:34])[C:10]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2[C:25]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:12]=2[N:11]=1>O1CCCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2[C:25]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:12]=2[N:11]=1)=[O:34]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of tert-butyl (2-{2-[(2,4-dichlorophenyl) (hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}ethyl)carbamate (500 mg, 0.985 mmol) and manganese(IV)oxide (856 mg, 9.85 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 4 h, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a yellow amorphous solid (404 mg, 0.800 mmol, 81%).
Reaction SMILES: C([NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1)(=O)C1C=CC=CC=1.[ClH:23]>C(O)(=O)C>[ClH:23].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nccc2cc(C(=O)O)ccc12
Temperature: 100 °C

Procedure:
A mixture of 445 mg [1-(benzoylamino)-6-isoquinolinyl]carboxylic acid, 10 mL of acetic acid and 20 mL of 4N hydrochloric acid was heated at 100° C. for one day. The reaction mixture was concentrated and coevaporated with 0.5N hydrochloric acid. The resulting residue was triturated with diethyl ether to yield 341 mg of the title compound. 1H-NMR 200 MHz (CD3OD) δ: 7.35 (1H, dd, J=1 Hz and J=7 Hz), 7.63 (1H, d, J=7 Hz), 8.30 (1H, dd, J=2 Hz and J=8 Hz), 8.49-8.57 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([C:48]1[C:49]([O:58][CH3:59])=[N:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([NH:44][CH2:45][C:46]([C:48]1[C:49]([O:58][CH3:59])=[N:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nc2ccccc2cc1C(=O)CN
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1cc2ccccc2nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A solution of (S)-2-((tert-butoxycarbonyl)amino)-8-oxodecanoic acid (0.76 mmol, 1 eq), EDC.HCl (0.99 mmol, 1.3 eq), HOBT (0.99 mmol, 1.3 eq) in DMF (3 mL) was stirred at room temperature for 10 min. A solution of 2-amino-1-(2-methoxyquinolin-3-yl)ethanone (1 eq) in 3 mL of DMF and DIPEA (2 eq) was added and the mixture was stirred at room temperature for 2 h. Mixture was diluted with DCM and washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated. Residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 10% EtOAc to 80% EtOAc), to isolate title compound in 20% yield. MS (ES) C27H37N3O6 requires: 499.60, found: 500.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>O1CCOCC1.C(O)(C)C>[NH:17]1[CH2:16][CH2:15][CH:14]([O:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][C:9]=2[O:27][CH3:28])[N:6]=[CH:5][N:4]=[C:3]3[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:30]([Cl:29])[C:31]=2[F:37])[CH2:19][CH2:18]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Temperature: 100 °C

Procedure:
4.0M HCl in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100° C. for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline as a di-hydrochloride salt (2.38 g); 1H NMR Spectrum: (DMSO d6) 1.84–1.99 (m, 2H), 2.22–2.33 (m, 2H), 3.12–3.33 (m, 4H), 4.00 (s, 3H), 5.08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8.84–8.94 (m, 2H), 8.99–9.11 (m, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[C:14]([C:19]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:20]=1[O:21][CH:22]([CH2:38][CH3:39])[C:23]([N:25]1[C:30]2[CH:31]=[C:32]([OH:36])[C:33]([NH2:35])=[CH:34][C:29]=2[O:28][CH2:27][C:26]1=[O:37])=[O:24])([CH2:17][CH3:18])([CH3:16])[CH3:15]>C1COCC1>[C:14]([C:19]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:45])[CH3:46])[CH:41]=[CH:40][C:20]=1[O:21][CH:22]([CH2:38][CH3:39])[C:23]([N:25]1[C:30]2[CH:31]=[C:32]([OH:36])[C:33]([NH:35][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=3)=[O:11])=[CH:34][C:29]=2[O:28][CH2:27][C:26]1=[O:37])=[O:24])([CH2:17][CH3:18])([CH3:16])[CH3:15]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc(N)c(O)cc21
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c(O)cc21
Reaction time: 1 h

Procedure:
4-Trifluoromethylphenylisocyanate (2.55 g, 0.0136 mole) was added to the amine ((g), 6.56 g, 0.0136 mole) in THF (ml 100). After 1 hour stirring, the solution was evaporated to dryness and the residue crystallized from toluene to give the coupler ((h), 6 g, 67%) as white prisms. The product structure was confirmed by NMR analysis.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH:30](C1N=C(C(O)=O)C(N)=C(C)N=1)(C)C>>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)([CH3:30])[CH3:2]
Reactant: Cc1nc(C(C)C)nc(C(=O)O)c1N
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)nc(NC(C)C)n1

Procedure:
rac-3-{4-[5-(2-Isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-isopropyl-amino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.85 min*; [M+H]+=414.12.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][N:16]=1.[H-].[Na+]>C1COCC1.CN(C=O)C.CCOCC>[F:21][C:20]1[C:15]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:16][CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Fc1cnc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ncc(F)cc2F)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.10 g, 5.89 mmol) and 2,3,5-trifluoropyridine (0.86 g, 6.48 mmol) in dry THF (20 mL) and dry DMF (4 mL), at rt was added 60% NaH in oil (0.35 g, 8.84 mmol). The mixture was stirred in a 40° C. oil bath overnight, cooled to rt, diluted with ether (175 mL), washed with water (25 mL) and brine (25 mL), and dried over Na2SO4. Removal of the solvent left a dark oil (1.94 g) which was purified by chromatography on a 40-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(3,5-difluoropyridin-2-yloxy)pyrrolidine-1-carboxylate (0.83 g, 47%). LC-MS Method 1 tR=1.85 min, m/z=301.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[C:15](=COC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=[O:40])C.O=[O+][O-]>CO>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([OH:40])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Agent: O=[O+][O-]
Solvent: CO
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
A solution of 4-nitrobenzyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (1.97 g), ethyl acetate (30 ml) and methanol (7.5 ml) was treated with ozone in a similar manner to that of Example 1 (4) to give 4-nitrobenzyl 7-(2-phenylacetamido)-3-hydroxy-3cephem-4-carboxylate (400 mg.).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:2]3[CH:15]=[CH:16][C:5]([CH3:6])=[CH:4][CH:3]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 122.4 %

Procedure:
A mixed solution of 2 g of 1,6-dibromopyrene, 1.9 g of 4-methylphenylboronic acid, 5.9 g of tripotassium phosphate, 0.9 g of tetrabutylammonium bromide, 15 mg of palladium acetate and 30 ml of dimethylformamide was heated while stirred under nitrogen gas stream at a temperature of 130° C. for 6 hours. After cooling the mixed solution to room temperature, 30 ml of water was injected thereinto and the resulting solution was filtered. The solid filtered off was washed with 30 ml of ethanol, and thereafter recrystallized from toluene and vacuum dried to thereafter obtain 1.3 g of 1,6-bis(4-methylphenyl)pyrene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:27])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]2[NH:14][N:15]=[C:16]([CH3:17])[C:11]2=[C:10]([CH2:18][N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH:21]([CH3:26])[CH2:20]2)[CH:9]=1.C1COCC1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34].CCN(C(C)C)C(C)C>O>[CH2:33]([NH:35][C:36]([N:22]1[CH2:23][CH2:24][CH2:25][N:19]([CH2:18][C:10]2[CH:9]=[C:8]([C:7]3[CH:6]=[CH:5][C:4]([OH:27])=[CH:3][C:2]=3[F:1])[N:13]=[C:12]3[NH:14][N:15]=[C:16]([CH3:17])[C:11]=23)[CH2:20][CH:21]1[CH3:26])=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CCCNC(C)C3)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)N1CCCN(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1C

Procedure:
To a solution of 75 mg 3-Fluoro-4-[3-methyl-4-(3-methyl-[1,4]diazepan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol in 1.5 ml abs. THF were added 15 mg ethyl isocyanate and 26 mg Hünig's base. After 16 h at rt water was added, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried and concentrated in vacuo. After purification by HPLC 29 mg (32%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][C:16]#[N:17])[C:6](=[O:18])[N:5]([CH2:19][C:20]#[N:21])[C:4]=2[N:3]=1.ClC1NC2C(=O)NC(=O)N(CC#N)C=2N=1>>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][C:16]#[N:17])[C:6](=[O:18])[N:5]([CH2:19][C:20]#[N:21])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CC#N)c(=O)n2CC#N
Agent: N#CCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Product: N#CCn1c(=O)c2[nH]c(Cl)nc2n(CC#N)c1=O

Procedure:
The title compound was prepared from 2,2′-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-6,7-dihydro-1H-purine-1,3(2H)-diyl]diacetonitrile using the conditions described for the synthesis of (8-chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)acetonitrile.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=2[C:20]([O:22]CC)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1=C(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)=C(C(=O)O)C1
Yield: 87 %

Procedure:
1-tert-Butyl 3-ethyl 4-phenyl-5,6-dihydropyridin-1,3(2H)-dicarboxylate (7.07 g) was dissolved in ethanol (50 ml), and thereto was added 1M aqueous sodium hydroxide solution (50 ml), and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and thereto was added 1M aqueous sodium hydroxide solution and ethyl acetate for separation. To the organic layer was added 1M aqueous sodium hydroxide solution for separation, and the aqueous layers were combined, and the pH value thereof was adjusted to pH<2 by the addition of 2M hydrochloric acid. The mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.63 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(-c2cccc(F)c2)coc2cc(O)ccc12
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(c1)OCC(c1cccc(F)c1)C2
Reaction time: 6 h

Procedure:
3-(3-Fluorophenyl)-7-hydroxychromen-4-one (160 mg) was dissolved in ethanol (40 ml) and 10% palladium on carbon (400 mg) was added. The reaction mixture was hydrogenated for 6 hours at normal pressure and room temperature. It was then filtered through Celite and washed with ethanol. The solvent was evaporated under reduced pressure to give 3-(3-fluorophenyl)chroman-7-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.19 (br s, 1H), 7.38 (m, 1H), 7.17-7.21 (m, 2H), 7.08 (m, 1H), 6.88 (d, 1H, J 8.2 Hz), 6.30 (dd, 1H, J 8.2, 2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.22 (dd, 1H, J 10.3, 3.6 Hz), 4.02 (t, 1H, 10.3 Hz), 3.20 (m, 1H), 2.90 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[NH2:21])[CH:16]=O.Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[NH2:21]
Reactant: Nc1ccc(C=O)cc1Cl
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: Nc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1Cl
Temperature: 25 °C
Yield: 91.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-chloro-4-aminobenzaldehyde 1.24 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 1.75 g.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]([CH3:23])[CH2:21][Cl:22]>CN(C)C=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][N:2]([CH2:19][CH:20]([CH3:23])[CH2:21][Cl:22])[CH3:1])=[CH:6][CH:7]=1
Reactant: CNCCc1ccc(Cl)cc1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CCl)CN(C)CCc1ccc(Cl)cc1

Procedure:
16.9 g (0.1 mol) of N-methyl-2-(4-chlorophenyl)ethylamine were dissolved in 30 ml of dimethylformamide and treated with 20.7 g (0.3 mol) of anhydrous potassium carbonate. The mixture was stirred at 5° and treated with 12.6 ml (0.11 mol) of 1-bromo-2-methyl-3-chloropropane, whereupon the mixture was stirred at 30° for a further 4 hours, the solvent was evaporated at 30° under reduced pressure and the residue was treated with water. The separated oil was extracted three times with ether. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was distilled at 135°-140°/260 Pa, whereby there was obtained rac-4-chloro-N-(3-chloro-2-methylpropyl)-N-methylphenethylamine as a colourless oil which was used directly in the next step. MS: 260 (M)+.