Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:32][C:33]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH2:37])=[O:36].N>N1C=CC=CC=1.CN(C=O)C>[NH2:32][C:33]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:38][CH:39]=[CH:40][C:41]=1[NH:42][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:31])=[CH:25][CH:24]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (27.5 mg, 0.1 mmol), as prepared in Example 1d, in anhydrous DMF, was added 4-dimethylamino-phenylisocyanate (25 mg, 0.15 mmol) and the mixture was stirred at rt overnight. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to yield 19 mg (44%) of pure 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-dimethylamino-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): 9.07 (s, 1H), 7.33 (s, 1H), 7.28-7.17 (m, 3H), 6.9-6.56 (bs, 2H), 6.50-6.22 (bs, 1H), 4.26 (m, 2H), 4.06 (s, 6H), 3.57 (m, 1H), 3.14 (m, 2H), 3.02-2.76 (m, 6H), 2.22-1.90 (m, 4H). LC/MS (ESI): calcd mass 435.2, found 436.5 (MH)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[CH2:29]([O:31][CH2:32][CH2:33]O)[CH3:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH2:29][O:31][CH2:32][CH3:33])=[O:23])=[CH:25][CH:26]=1
Reactant: CCOCCO
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Reaction time: 120 h

Procedure:
A solution of 11.5 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred at reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 73A (0.28 g, 0.441 mmol) in a mixture of THF (5 mL), methanol (5 mL), and aqueous HCl (5 mL, 1 N) was stirred at 60° C. for 16 hours, and concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:44][CH2:45][N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCN1CCOCC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol), (prepared as described for the starting material in Example 107), triphenylphosphine (235 mg, 0.89 mmol) and 4-(2-hydroxyethyl)morpholine (93 mg, 0.72 mmol) in methylene chloride (4 ml) cooled at 10° C. was added diethyl azodicarboxylate (140 μl, 0.89 mmol). After stirring at ambient temperature for 3 hours, the mixture was left overnight at 5° C. The mixture was poured onto a column of silica and eluted with methylene chloride followed by methanol/methylene chloride (2/98) followed by 3N ammonia methanol/methylene chloride (2/98). The fractions containing the expected products were combined and evaporated to give 4-(indol-5-yloxy)-6-methoxy-7-(2-morpholinoethoxy)quinazoline (137 mg, 55%).
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>>[C:29]([S:31][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:32])[CH3:30].[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: BrCCCCCCCCCCCCCCCC[c-]1cccc1
Reactant: CC([O-])=S
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Product: CC(=O)SCCCCCCCCCCCCCCCC[c-]1cccc1
Yield: 89.7 %

Procedure:
16-Ferrocenylhexadecyl bromide 26 (1.1 g, 2.3 mmol) was treated with potassium thioacetate (0.4 g, 3.5 mmol) for 20 h following the same procedure described for 27 to afford yellow crystals (1.0 g, 93%): mp 55–57° C.; 1H NMR δ 1.25 (s, 22H), 1.51 (m, 2H), 2.30 (m, 2H), 2.32 (s, 3H), 2.86 (m, 2H), 4.04 (s, 2H), 4.05 (s, 2H), 4.09 (s, 5H); 13C NMR δ 29.5, 29.8, 30.2, 30.3, 30.3, 31.8, 67.7, 68.8, 69.2, 90.0, 197.5; FAB-MS obsd 484.2518, calcd exact mass 484.2514; Anal. Calcd for C28H44FeOS: C, 69.40; H, 9.15; Found: C, 69.45; H, 9.07.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]#[N:11].[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:11][C:10]1[C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(Cl)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2ccc(C#N)cc2c1N
Yield: 37 %

Procedure:
4-Chloroisophthalonitrile (5.69 g, 35 mmol), prepared by the method of Markley et al, J. Med. Chem., 29: 427 (1986), was treated with 1 equivalent methyl thioglycolate and 1 equivalent Na2CO3 in methanol by the procedure described in Example 41A to yield the title compound (3.00 g, 37%). m.p. 248° C. 1H NMR (300 MHz, DMSO) δ 8.71 (s, 1H), 8.09 (d, 1H), 7.86 (dd, 1H), 7.30 (br s, 2H), 3.81 (s, 3H). MS (DCI/NH3) m/e 250 (M+NH4)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[NH2:10][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12]1>>[CH3:12][C:11]([NH:10][CH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:13])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Product: CCOC(=O)C(C)(C)NCc1cccnc1
Yield: 95 %

Procedure:
Prepared as in Example 12-1b from nicotinaldehyde and ethyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 95%, a white solid. MS 223 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:10]([O-:13])(O)=[O:11]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:3][C:4]=2[CH:9]=1)([O-:13])=[O:11]
Reactant: c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1)OC(c1ccccc1)O2
Temperature: 0 °C

Procedure:
A solution of 39.6 g (0.2 mol) of the benzodioxolan obtained as just described in 150 ml of acetic acid ester was added dropwise at 25° to 35° C. to 150 ml of a 33% nitric acid. The solution was poured into ice water after 2 hours and then extracted several times with acetic ester. The combined acetic ester phases were then washed several times with a solution of potassium bicarbonate and then with water, followed by drying and evaporation by concentration. Crystallization from ethanol furnished 37 g of a product of the melting point between 84° and 85° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether was treated with 9.7 g of potassium t-butylate at -10° C. within 3 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The orange suspension was stirred at about 0° C. for 1 hour, then treated dropwise at -10° C. within 10 minutes with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and stirred at 0° C. for a further 45 minutes. The reaction mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate filtered and evaporated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and evaporated. Chromatographic separation of the yellowish, crystalline residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])N.[K+].O>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-2-methylnitrobenzene (2 g), 1,2,4-triazole (0.9 g) and anhydrous potassium carbamate (1.78 g) was stirred and heated in dimethylsulphoxide (50 ml) at 90° C. for 24 hours. The reaction mixture was cooled, poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to give an orange solid which was purified by chromatography on silica using pentane/ethyl acetate as eluant, (1.8 g, 69%).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:18]([NH2:20])=[O:19])=[C:5]([F:34])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:41]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:34])=[CH:4][C:3]([C:1]([NH2:2])=[O:41])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (12 mg, 0.025 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (6 mg). MS 491.1 (M+H); UV 216.8, 278.0, 312.5 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12].S(OC)(O[CH3:21])(=O)=O>[OH-].[Na+]>[CH3:21][O:12][C:11]1[C:10]([CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=1[O:5][C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([Cl:1])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(Oc2cccc(Cl)c2)c1O
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cccc1Oc1cccc(Cl)c1

Procedure:
An aqueous solution (40 ml) of sodium hydroxide (10 g) and a mixture of 6-(3-chlorophenoxy)-o-cresol (13.9 g) and dimethyl sulfate (11 ml) were treated in a similar manner to that of Example 6-(2) to give oily 3-chlorophenyl 2-methoxy-3-methylphenyl ether (14.6 g).
Reaction SMILES: C([O-])=O.[K+].C(O)=O.O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1>[Pd].O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 60 °C
Yield: 82.6 %

Procedure:
A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium on carbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 60° C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60° C. When the reaction was deemed complete as determined using in-process HPLC analysis (<2% starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35° C. to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50° C. to afford the title compound (3.0 kg; 97% AUC).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[O:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:25]4[CH:26]=[CH:27][O:23][CH:24]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccoc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccoc4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of 3-furaldehyde to form 4-(3-chloro-phenylamino)-3-[(fur-3-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)-3-[(fur-3-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 207-209° C.; HPLC: tRet(grad20-100/20)=8.4; MS: (M)+=340, (M−H)+=339.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].C[Si]([N:25]=[N+:26]=[N-:27])(C)C.C([Sn](=O)CCCC)CCC.O1CCCC1>C(OCC)(=O)C>[N:2]1[NH:25][N:26]=[N:27][C:1]=1[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc2cc(-c3nn[nH]n3)[nH]c12)c1cccs1
Yield: 23 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.40 g), trimethylsilylazide (0.35 mL), dibutyltin oxide (33 mg) and tetrahydrofuran (15 mL) was heated under reflux overnight. To the reaction mixture was added ethyl acetate, the mixture was ice-cooled, and the resulting crystals were filtrated, washed with cold ethyl acetate, and dried to give the title compound (0.09 g, yield 23%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 274-275° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[O:21][CH2:22][CH:23]([F:25])[F:24])=[CH:4][CH:3]=1>[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[O:21][CH2:22][CH:23]([F:25])[F:24])=[CH:6][CH:7]=1
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N

Procedure:
The subtitle compound is prepared from N-(4-bromophenyl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-nitro-benzamide, RaNi and H2 in analogy to example 5c.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([C:15]1([CH2:30][CH3:31])[CH2:20][CH2:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH2:16]1)[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.COCCOC>[CH2:13]([C:15]1([CH2:30][CH3:31])[CH2:20][CH2:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[CH:17][CH2:16]1)[CH3:14]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCC1(CC)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCC1(CC)CC=C(c2ccc(OC)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-nitroanisole (2 g, 8.62 mmol), 2-(4,4-diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.7 g, 10.3 mmol) prepared in Example (6c), tripotassium phosphate (2.7 g, 13.0 mmol) and 1,2-dimethoxyethane (20 mL) was stirred at room temperature under a nitrogen atmosphere, and then tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmol) was added. The mixture was then stirred at an external temperature of 80° C. for 26 hours.
Reaction SMILES: Br[CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].C([O-])(=[O:16])C.[Na+]>C(O)(=O)C>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:16])[CH3:3]
Reactant: CC(Br)c1ccc2ccccc2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1'-bromoethyl)naphthalene, prepared as described above, wtih sodium acetate in acetic acid to afford 2-(1'-acetonyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1'-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C>O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:18]2[N:17]=[C:16]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:21]([Br:22])=[CH:20][N:19]=2)=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reaction time: 2 h
Yield: 70.2 %

Procedure:
Sodium hydrosulphite (9.5 g, 54.5 mmol) was added over 30 minutes to a stirred solution of anilino-5-bromo-2-(4-nitroanilino)pyrimidine (Method 39; 7.0 g, 18.2 mmol) in a hot mixture of ethanol and water (1:1, 100 ml). The resulting suspension was stirred for a further two hours and insoluble material was removed by filtration. The filtrate was concentrated and the residue was partitioned between 1M aqueous sodium hydroxide (50 ml), and DCM (100 ml). The organic layer was separated, washed with water (2×10 ml) and dried. Volatile material was removed by evaporation to give the product (4.55 g, 70%). MS (MH+): 356, 358.