Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:21][C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:26]=3)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[C:5]([CH3:33])[O:4][N:3]=1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([NH:21][C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:26]=3)[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)=[C:5]([CH3:33])[O:4][N:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)Nc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(C)c1COc1ccc(C[C@H](Nc2nc(-c3ccccc3)cs2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The crude product from Step B was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added, and the mixture extracted with ethyl acetate. The solvent was evaporated.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].C(O)C.[CH2:15]([N:17]([CH2:20][CH2:21]Cl)[CH2:18][CH3:19])[CH3:16]>[OH-].[Na+]>[CH2:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH2:19][N:8]1[C:9]2[C:10](=[O:11])[NH:1][C:2](=[O:3])[NH:4][C:5]=2[N:6]=[CH:7]1)[CH3:16]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: CCN(CC)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Yield: 15 %

Procedure:
Xanthine (30.4 g) was dissolved in aqueous sodium hydroxide solution (8 g in 500 ml) containing ethanol (100 ml). The solution was stirred, and diethylaminoethyl chloride (liberated from its salts) (27.0 g) was added at room temperature. The mixture was stirred on a steam bath for 18 hours, then evaporated to dryness. The residue was fractionally recrystallised from isopropyl alcohol to give 7-(2-diethylaminoethyl)xanthine (7.5 g). The solid was stirred in dry tetrahydrofuran (1 liter) at -15° C. under nitrogen. Butyl lithium (90 ml) was then added by syringe, and the mixture was stirred for 2 hours. Methyl iodide (12.8 g) was then added and the mixture was stirred and allowed to warm to room temperature. It was then stirred overnight, quenched with water and extracted with chloroform. The extracts were then washed, dried, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in ethanol and treated with ethanolic hydrogen chloride, then evaporated to dryness. The residue was recrystallised from isopropyl alcohol to give 8-methyl-7-(2-diethylaminoethyl)theophylline hydrochloride (3.1 g), mp 230°-232° C.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:24])([F:23])[C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15].[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C(O)(=O)C>[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CNC2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol) and N-trifluoroacetyl-4-piperidone (from reaction step 1) (5.065 g, 25.9 mmol) were added to a 250 ml round-bottomed flask and dissolved in the methanol/acetic acid (150 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBH3 (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a reparatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO4. Concentration afforded, 4-(4-methylbenzylamine)-1-(trifluoroacetyl) piperidine. UV/MS 60/53 (M+ 301), tr (A, MS) 3.267.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH2:10]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:10]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[OH:9])=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: NO
Reactant: CCCCCCCCCCCCc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc(CN(O)Cc2ccc(CCCCCCCCCCCC)cc2)cc1
Reaction time: 8 h

Procedure:
The procedure of Example 1 is repeated using 16.0 g of sodium carbonate, 2.57 g of hydroxylamine hydrochloride and 21.83 g of p-dodecylbenzyl chloride in 75 ml of dimethylformamide kept at 50°-55° C. overnight under nitrogen. The product is isolated as a light brown oil.
Reaction SMILES: [N:1]1(O)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+].[C:49]([C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]([CH3:91])[C:61]([S:64][C:65]3[CH:82]=[CH:81][C:68]([CH2:69][NH:70][C:71]4[CH:76]=[CH:75][C:74]([CH2:77][C:78](O)=[O:79])=[CH:73][CH:72]=4)=[C:67]([O:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH3:90])[CH:66]=3)=[N:62][N:63]=2)=[CH:55][CH:54]=1)([CH3:52])([CH3:51])[CH3:50]>CN(C)C=O.O>[C:49]([C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]([CH3:91])[C:61]([S:64][C:65]3[CH:82]=[CH:81][C:68]([CH2:69][NH:70][C:71]4[CH:76]=[CH:75][C:74]([CH2:77][C:78]([NH2:1])=[O:79])=[CH:73][CH:72]=4)=[C:67]([O:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH3:90])[CH:66]=3)=[N:62][N:63]=2)=[CH:55][CH:54]=1)([CH3:51])([CH3:50])[CH3:52]
Reactant: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
152 mg (1.12 mmol, 1.5 eq) of benzotriazol-1-ol, 497 mg (1.12 mmol, 1.5 eq) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 780 μl (4.50 mmol, 4 eq) of diisopropylethylamine and finally 80 mg (1.50 mmol, 2 eq) of ammonium chloride are added to a solution of 450 mg (0.75 mmol, 1 eq) of (4-{4-[5-(4-tert-butylphenyl)-4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl]-2-heptyloxybenzyl amino}phenyl)acetic acid in 6 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 24 hours, and then supplemented with a small amount of water. The precipitate obtained is filtered, dried and chromatographed on a silica gel cartridge (heptane/ethyl acetate 30/70). 298 mg (66%) of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.[C:31]1(=O)[CH2:34][CH2:33][CH2:32]1.C(O[BH3-])(=O)C.[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH:31]1([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10]([C:8]([N:5]3[CH2:6][CH2:7][C:2]([F:1])([F:26])[CH2:3][CH2:4]3)=[O:9])=[CH:18]4)[CH2:21][CH2:22]2)[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(c1cc2cc(OC3CCNCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: O=C1CCC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1cc2cc(OC3CCN(C4CCC4)CC3)ccc2[nH]1)N1CCC(F)(F)CC1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A mixture of (4,4-difluoro-piperidin-1-yl)-[5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone (example 43, step 6, 350 mg, 1.0 eq.), acetic acid (0.17 mL, 3.0 eq.) and cyclobutanone (138 mg, 2.0 eq.) in tetrahydrofuran (6 mL) was stirred at 55° C. for 1 h. At room temperature, sodium acetoxyborohydride (421 mg, 2.0 eq.) was added and the mixture stirred for 16 h at 65° C. The reaction mixture was partitionned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic fractions were washed twice with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 49:1:0 to 95:5:0.25 gradient of dichloromethane/methanol/ammonium hydroxide, to yield 265 mg (65%) from the desired product as off-white solid. MS (m/e): 418.1 (MH+, 100%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[N:23][C:24]([C:27](=[O:34])[NH:28][CH2:29][CH2:30][CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:14]>O1CCCC1.O>[CH:31]1([CH2:30][CH2:29][NH:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:6]([OH:35])=[O:5])=[O:14])[CH2:20][CH2:19]3)=[CH:26][CH:25]=2)=[O:34])[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(=O)O)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Lithium hydroxide monohydrate (0.066 g, 1.57 mmol) was added to a solution of 2-{4-[6-(2-cyclopropylethylcarbamoyl)pyridazin-3-yl]piperazine-1-carbonyl}benzoic acid methyl ester (0.230 g) in tetrahydrofuran (10 mL) and water (5 mL) stirred at ambient temperature overnight. THF was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), neutralized by addition of 5% HCl solution, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from dichloromethane and hexanes to yield 0.107 g of the title compound (42% yield). 1H NMR (300 MHz, CDCl3) δ 8.67, 9.07-7.87, 7.54, 7.41, 7.26-7.24, 6.95, 4.12-3.27, 1.55-1.40, 0.77-0.64, 0.50-0.34, 0.13-0.01; 13C NMR (75 MHz, CDCl3) δ 170.7, 168.2, 163.2, 159.9, 145.0, 137.7, 133.1, 131.2, 129.2, 127.9, 127.2, 126.6, 112.6, 46.2, 44.1, 41.4, 39.7, 34.4, 8.6, 4.2; MS (ES+) m/z 424.2 (M+1).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH:9]1([C:12]2[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[CH2:11][CH2:10]1>C(O)C>[CH:9]1([C:12]2[N:17]=[C:16]([C:18]([NH2:19])=[O:2])[CH:15]=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:13]=2)[CH2:11][CH2:10]1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(C(F)(F)F)cc(C2CC2)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)cc(C2CC2)n1
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To 7 ml of ethanol were added 0.58 g of sodium bicarbonate and 0.48 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.6 g of 6-cyclopropyl-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 4 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 6-cyclopropyl-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: C(OC(N1CCC[C@@H]1C(O)=O)=O)(C)(C)C.COC1C=C(C=C(OC)C=1OC)C(O)=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(OC([N:60]1[CH2:64][CH2:63][CH2:62][CH:61]1[CH2:65][CH2:66][N:67]([CH2:82][C:83]([CH3:91])=[CH:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[C:68](=[O:81])[C:69]1[CH:74]=[C:73]([O:75][CH3:76])[C:72]([O:77][CH3:78])=[C:71]([O:79][CH3:80])[CH:70]=1)=O)(C)(C)C>O1CCOCC1.Cl.C(N(CC)CC)C>[CH3:80][O:79][C:71]1[CH:70]=[C:69]([CH:74]=[C:73]([O:75][CH3:76])[C:72]=1[O:77][CH3:78])[C:68]([N:67]([CH2:82][C:83]([CH3:91])=[CH:84][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)[CH2:66][CH2:65][C@H:61]1[CH2:62][CH2:63][CH2:64][NH:60]1)=[O:81]
Reactant: COc1cc(C(=O)N(CCC2CCCN2C(=O)OC(C)(C)C)CC(C)=Cc2ccccc2)cc(OC)c1OC
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(CC[C@H]2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 39 %

Procedure:
Experimental condition analogous to Example 13 were used with 2-[2-(2-Methyl-3-phenyl-allylamino)]-ethyl-(R) pyrrolidine-1-carboxylic acid tert-butyl ester (prepared from (R)-Pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester according to the scheme 3) 0.6 g (2 mmol), 3,4,5-trimethoxy benzoic acid 0.51 g (2.4 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 1.3 g (4 mmol) and triethylamine 0.2 ml. The intermediate 2-{2-[(2-methyl-3-phenyl-allyl)-(3,4,5-trimethoxy-benzoyl)-amino-]-ethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 10 ml of dioxane and 5 ml of 6 N HCl, yielding 0.35 g of the compound after basic work-up and purification. Yield: 39%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][N:28]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: Cc1ccc(CN)nc1
Solvent: COCCOC
Product: Cc1ccc(CNc2cc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and C-(5-methyl-pyridin-2-yl)-methylamine in DME. ES-MS m/e (%): 328 (M+Na+, 30), 306 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>N1C=CC=CC=1>[S:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1)([CH3:21])(=[O:24])=[O:23]
Reactant: O=C1NCC[C@@H](c2ccc(O)cc2)[C@@H]1c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Oc1ccc([C@@H]2CCNC(=O)[C@H]2c2ccccc2)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1.34 g (0.005 mol) of 27 in 10 cm3 of anhydrous pyridine, 1.14 g (0.01 mol; 0.77 cm3) of methanesulfonyl chloride are added under an atmosphere of nitrogen at 0° C. The mixture is stirred for 1 hour at between 0° and 3° C. before being poured into 70 cm3 of cold water. This mixture is extracted with methylene chloride and washed to neutrality. After evaporation and recrystallization in methanol, 29 is obtained in 61% yield. M.p. 199° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=[CH:11][C:6]=2[CH:5]=[N:4][CH:3]=1.CO.C(=O)([O-])[O-].[Na+].[Na+].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.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.CC(=O)OCC.O>[N:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:7]3[C:8](=[O:24])[N:9]([CH2:12][CH2:13][C:14]4[CH:23]=[CH:22][C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=4)[N:10]=[CH:11][C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: O=c1c2c(Cl)cncc2cnn1CCc1ccc2ccccc2n1
Reactant: OB(O)c1ccncc1
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: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=c1c2c(-c3ccncc3)cncc2cnn1CCc1ccc2ccccc2n1
Temperature: 130 °C
Yield: 6.8 %

Procedure:
8-chloro-2-(2-(quinolin-2-yl)ethyl)pyrido[4,3-d]pyridazin-1(2H)-one (34 mg, 0.101 mmol) was suspended in 2 mL of toluene and 2 mL of methanol under argon. Then, an aqueous solution of sodium carbonate (16.5 mg, 0.15 mmol, 2 M) was added. To the suspension, pyridin-4-boronic acid (13.79 mg, 0.101 mmol) and then tetrakis(triphenylphosphine)palladium(0) (11.67 mg, 10.10 μmol) were added. The reaction mixture was heated in a CEM microwave at 130° C. for 30 min. Water and EA were added. The organic phase was extracted with water, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluent: DCM/methanol) and then recrystallized from EA/diisopropyl ether (1:1) to give 2.6 mg (yield: 6.79%) of the title compound as off-white solid. LC-MS: m/e 380.1 (M+H)+
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:27][OH:28].[OH-].[Na+].C1COCC1>CO>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:27][OH:28])=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Yield: 26 %

Procedure:
Title compound 350 (147 mg, 0.43 mmol), hydroxylamine (50% in water, 6 mL) and sodium hydroxide (138 mg, 3.40 mmol) were stirred in methanol (3 mL) and THF (3 mL) at room temperature overnight. The organic solvent was evaporated and the precipitate was filtered off and washed with a little bit of cold methanol to afford title compound 351 (39 mg, 26%) as a yellow solid. 1H NMR (DMSO-d6) δ (ppm): 11.06 (s, 1H), 8.96 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.21 (td, J=1.6 and 7.2 Hz, 2H), 7.18-7.13 (m, 2H), 7.10 (dd, J=1.6 and 7.6 Hz, 2H), 6.6 (td, J=1.2 and 7.2 Hz, 2H), 6.85 (s, 2H), 5.00 (s, 2H). LRMS: 342.1 (calc) 343.2 (found)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH:5]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].Cl>O1CCCC1.CCCCCC>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([CH:30]=[O:31])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(Br)c2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(C=O)c2)CC1
Temperature: -78 °C

Procedure:
1-(3-Bromo-4'-chlorobenzhydryl)-4-methylpiperazine (see U.S. Pat. No. 4,757,074) (1.00 g, 2.63 mmole) was dissolved in 12 ml of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.1 M n-butyllithium in hexane (2.4 ml) was added dropwise and the reaction was stirred for ten minutes. N,N-Dimethylformamide (0.25 ml, 3.2 mmole) was added in one portion and the reaction was allowed to warm to -40° C. Hydrochloric acid (1.0M, 20 ml) was added and the reaction was warmed to room temperature. The solution was washed with 20 ml of diethyl ether and the ethereal wash was discarded. The aqueous solution was made basic with aqueous sodium hydroxide and extracted with two 15 ml portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and the solvent removed to give 738 mg of crude 1-(4-chloro-3'-formylbenzhydryl)-4-methylpiperazine as a dark oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.I/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>CS(C)=O.[Cl-].[Cr+2].[Cl-].[Ni](Cl)Cl>[OH:16][CH:15]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH:14]=1)/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)/C=C/I
Reactant: O=Cc1ccc2nc(-c3cccs3)oc2c1
Agent: Cl[Ni]Cl
Agent: [Cr+2]
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/C(O)c1ccc2nc(-c3cccs3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.2 g (5.23 mmol) 2-thiophen-2-yl-benzoxazole-6-carbaldehyde and 2.5 g (11.06 mmol) ethyl (E)-3-iodoacrylate in DMSO is added dropwise at RT to 4.0 g (32.55 mmol) chromium-(II)-chloride and 10 mg (0.08 mmol) nickel-(II)-chloride. The reaction mixture is stirred overnight at RT, then combined with sat. ammonium chloride solution and extracted 3× with DCM. The combined org. phases are concentrated by rotary evaporation i. V. and the residue is purified on silica gel (eluant: cyclohexane/EA).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)=[O:10])[CH:2]=1>CCOC(C)=O.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(C(=O)C=Cc2cccnc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)CCc2cccnc2)c1
Reaction time: 15 h
Yield: 99.6 %

Procedure:
A mixture of 17 (1.70 g, 5.0 mmol) and 10% Pd/C (85 mg) in EtOAc (70 mL) was hydrogenated in a Parr under H2 at 42 psi for 15 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. Chromatography on silica (50-60% EtOAc/hexanes) gave 1.70 g (100%) of a colorless oil. 1H NMR (CDCl3, 300 MHz) 8.54 (d, J=2.0 Hz, 1H), 8.48 (dd, J=4.8, 1.5 Hz, 1H), 7.70-7.10 (m, 6H) 4.58 (s, 2H), 3.31 (t, J=7.3 Hz, 2 H), 3.09 (t, J=7.4 Hz, 2H), 1.50 (s, 9H); 13C NMR (CDCl3, 75 MHz) 198.3, 168.0, 158.6, 150.4, 148.1, 138.4, 136.9, 136.4, 130.2, 123.7, 121.8, 120.7, 113.5, 83.0, 66.1, 40.2, 28.4, 27.5.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>O>[CH3:18][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cccc2[nH]c(S)nc12
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cccc2[nH]c(SC)nc12
Reaction time: 20 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (500 mg) were added iodomethane (351 mg) and potassium carbonate (622 mg) at ambient temperature and the mixture was stirred for 20 hours at same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-methylthio-1H-benzimidazole-4-carboxylate (310 mg).
Reaction SMILES: Cl.[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([OH:18])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1.Cl[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([O:18][CH2:34][CH2:33][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1
Reactant: CCC(Cl)C(=O)OC
Reactant: COc1c(O)ccc2c1N=C(C=C(O)c1cccnc1)N1CCN=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc2c(c1OC)N=C(C=C(O)c1cccnc1)N1CCN=C21
Temperature: 120 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A mixture of 5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol hydrochloride (Example 1-4) 50.4 mg (0.14 mmol), methyl chloro-butyrate 22.2 mg (0.16 mmmol) and potassium carbonate 186.9 mg (1.35 mmmol) in N,N-dimethylformamide 1 mL was stirred at 120° C. for 4 hours. The reaction mixture was poured into water and extracted into dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed by diethyl ether to give the title compound 35.0 mg as yellow solid. Yield 59.3%.