Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([O:12]CC)=O)=[N:4]1)[CH3:2].[OH-].[NH4+:16]>>[CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([NH2:16])=[O:12])=[N:4]1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(CC)n(CC)n1
Agent: [OH-]
Product: CCc1cc(C(N)=O)nn1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 1,5-diethyl-1H-pyrazole-3-carboxylate (29.4 g, 0.150 mol) and ammonium hydroxide (150 mL of 30%) was stirred overnight at ambient temperature. An analysis by thin layer chromatography (TLC) indicated the reaction was incomplete. The reaction was then heated for 14 hours at 125° C. in a pressure vessel, allowed to cool to ambient temperature, and cooled to 0° C. A precipitate formed, was isolated by filtration, and washed with cold hexanes to provide 8.3 g of 1,5-diethyl-1H-pyrazole-3-carboxamide as a white solid, mp 129-131° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:10][CH2:11][OH:12].CS(C)=O.[H-].[Na+]>O>[CH3:6][O:5][C:3]1([C:2]([F:8])([F:7])[F:1])[O:12][CH2:11][CH2:10][O:4]1
Reactant: COC(=O)C(F)(F)F
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A mixture of 42.0 g (0.33 mol) of methyl trifluoroacetate, 26.6 g (0.33 mol) of 2-chloroethanol, and 150 mL of dimethylsulfoxide (DMSO) was stirred at 10°-20° while 15.8 g (0.33 mol) of 50% NaH in mineral oil was added portionwise. The resulting mixture was stirred at 20° for 2 h, at 25° for several days, and then poured into 1 L of water. The resulting aqueous layer was extracted with 100 mL of ether. The organic layers were combined, then washed twice with water, dried over CaSO4, and distilled to give 35.6 g (63% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 60°-65° at 3.3 kPa (25 mm), and a residue containing about 4.8 g (7% yield) of by-product 2-(2-chloroethoxy)-2-trifluoromethyl-1,3-dioxolane (estimated by GC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([O:21][CH2:22][CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[F:20]>[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([O:21][CH2:22][CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:20]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1ccc(O)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], (2S)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([C@:27]2([NH:34][C:35]([NH2:37])=[S:36])[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2O)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([C:27]23[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[S:36][C:35]([NH2:37])=[N:34]3)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=S)N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1=NC2(c3cccc(Br)c3)CCOCC2S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Diethyl azodicarbonate (13.0 mL) was added dropwise to a solution of triphenylphosphine (7.51 g) in tetrahydrofuran (200 mL) in an ice bath. The mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled to 0° C., and a solution of (±)-[(3R*,4R*)-4-(3-bromophenyl)-3-hydroxytetrahydropyran-4-yl]thiourea (6.33 g) in tetrahydrofuran (44 mL) was added dropwise. The mixture was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was purified by silica gel column chromatography again to obtain the title compound (3.55 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].[F:37][CH:38](O)[CH3:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:39][CH2:38][F:37])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25]
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: CC(O)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCCF)ccc3n(C3CCOCC3)c2=O)cc1OC
Yield: 95.4 %

Procedure:
A mixture of 0.2 g of 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione and 0.32 g of Cs2CO3 in 10 ml of DMF is irradiated in a microwave field for 1 minute at 100° C. 0.169 g of fluoroethanol are then added and the mixture is irradiated in a microwave field for 5 minutes at 140° C. The reaction medium is evaporated under reduced pressure. The residue is taken up in EtOAc and washed with water and then with saturated NaCl solution. The resulting solution is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (80/20, v/v) to give 0.212 g of the expected product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Oc1ccccc1OCCCCCBr
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccccc1OCCCCCBr
Yield: 66.4 %

Procedure:
A mixture of 2.6 g (10 mmol) of 2-[(5-bromopentyl)oxy]phenol, 1.8 g (12 mmol) of methyl bromoacetate, 4.4 g (32 mmol) of anhydrous granular potassium carbonate, and 60 mL of dry acetonitrile was stirred and refluxed for 20 hr. The mixture was cooled and filtered with suction. The solids were washed with ether and the filtrate and washes were combined and concentrated in vacuo. The oily residue was purified by flash chromatography on silica gel, eluting with 3:1 hexane-ether. There was obtained 2.2 g (66.5%) of [2-[(5-bromopentyl)oxy]phenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][OH:28])=[NH:26])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:34][C:35](=[O:39])[C:36](Cl)=O)[CH3:33].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:32]([O:34][C:35]([C:36]1[O:28][N:27]=[C:25]([C:24]2[CH:29]=[CH:30][CH:31]=[C:22]([C:6]3[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]4[CH:10]=[CH:11][C:12]([C:14]5[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=5)=[CH:13][C:8]=4[N:7]=3)[CH:23]=2)[N:26]=1)=[O:39])[CH3:33]
Reactant: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C(=N)NO)c2)n3C(C)(C)C)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cccc(-c3nc4cc(-c5cncc(OC)c5)ccc4n3C(C)(C)C)c2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
3-[1-tert-Butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (0.500 g, 1.20 mmol) is dissolved in DMF (5 mL). Chloro-oxo-acetic acid ethyl ester (0.177 g, 1.30 mmol) is added followed by diisopropyl-ethylamine (1.5 mL). The reaction mixture is stirred at room temperature for 2 hours then heated at 110° C. for 16 hours. The solvent is removed in vacuum. The residue is purified by flash chromatography (silica gel 40 g, eluted with 0-100% ethyl acetate in hexane) to give the title compound (0.454 g, 76%). LCMS (ESMS): m/z 498.61 (M++1).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C)C=O>[CH2:21]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH:20]=[CH2:19]
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(CCCC)Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of 2-butyl-5-methoxy-1-indanone (500 mg, 2.3 mmol) in anhydrous N,N-dimethylformamide (DMF, 5 mL) was added to a suspension of sodium hydride (100 mg of a 60% dispersion in mineral oil, 2.5 mmol) in DMF (5 mL). The mixture was diluted with more DMF (2 mL, used to rinse in the indanone solution), placed under a nitrogen atmosphere, and stirred at room temperature for 25 minutes. Allyl iodide (0.32 mL, 3.5 mmol) was then added over 5 minutes, during which time the mixture clarified. After stirring at room temperature for an additional 15.5 hours, the mixture was partitioned between EtOAc (200 mL) and water (150 mL) containing brine. The aqueous phase was extracted with EtOAc (2×100 mL). The combined EtOAc solution was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to afford an oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4.0×7.0 cm) silica gel column, eluting with 49:1 hexanes-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-allyl-2-butyl-5-methoxy-1-indanone as an oil.
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH3:20])=[O:19])[CH2:13][CH2:12]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[O:1]([CH2:8][CH:9]([N:11]1[CH2:12][CH2:13][N:14]([CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]([OH:19])[CH3:20])[CH2:15][CH2:16]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(c1ccccc1)N1CCN(C(C)COc2ccccc2)CC1
Solvent: CO
Product: CC(O)C(c1ccccc1)N1CCN(C(C)COc2ccccc2)CC1
Reaction time: 24 h

Procedure:
To 1-[N(1-phenoxy-2-propyl)piperazino]-1-phenyl-acetone (1 mole) dissolved in methanol (1000 ml) is added BH4K (1 mole), portionwise at 0° C. Stirring is continued during 24 hours at room temperature. The methanol is removed in vacuo and the residue is taken up into ether and water. The ether phase is washed with water to neutral pH. The ether is evaporated off. The resulting white precipitate is taken up into ethanol to which is added an ethereal solution of hydrochloric acid. The white crystals obtained after recrystallization from ethanol melt at 237°-240° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.CO>[Pd].C1C=CC=CC=1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:2]2([CH3:1])[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][C:8]=3[CH3:12])[O:3]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C)c2c(c1)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: Cc1cc(C)c2c(c1)OC(C)(COc1ccc(N)cc1)CC2
Yield: 75 %

Procedure:
Following a procedure similar to that described in Preparation 4, 2.1 g of 2,5,7-trimethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 25) were hydrogenated at atmospheric pressure, using 200 mg of 10% w/w/ palladium-on-carbon, 20 ml of methanol and 50 ml of benzene, to afford 1.44 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)CCC>[CH2:4]([O:14][C:13](=[O:15])[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1])[CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)CN1C(=O)c2ccccc2C1=O
Reaction time: 24 h
Yield: 194.4 %

Procedure:
A mixture of 160 ml of butanol, 20.0 g of (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid (94.6 mmol) and 2.0 ml of concentrated sulfuric acid was refluxed with stirring for 24 h. Then 5 g of sodium bicarbonate were added in portions, stirring continued at r.t. for 5 min and the solvent evaporated in vacuo. The residue was partitioned between 100 ml of water and 100 ml of ethyl acetate. The organic phase was washed with 100 ml of brine, dried over sodium sulfate and was evaporated in vacuo to give a yellowish oil that later solidified. 24.02 g of the title compound were obtained; MS-(+)-ion: M+1=261.9 amu.
Reaction SMILES: [Al:1].[CH:2]([OH:5])([CH3:4])[CH3:3]>>[O:5]([Al:1]([O:5][CH:2]([CH3:4])[CH3:3])[O:5][CH:2]([CH3:4])[CH3:3])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)O
Reactant: [Al]
Product: CC(C)O[Al](OC(C)C)OC(C)C
Yield: 90 %

Procedure:
360 g anhydrous isopropanol, 0.0959 g mercuric salt and 13.5 g metallic aluminium scraps was refluxed at 83°-90° C. for 2-8 hours, evaporated off excess isopropand under normal pressure, triisopropoxyl aluminum was obtained by collecting distillation fraction of 110°-200° C. under reduced pressure of 1-10 mmHg. yield 90-100%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4].[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4'-(2-Bromoacetyl)methanesulfonanilide (Temple, D. L. et al., J. Med. Chem., 19(5), 626-633 (1976)) (40 g) and dibenzylamine (Aldrich Chemical Co., Milwaukee, Wis. 53233) (55.2 g) were combined in acetone (550 ml) and stirred 3 hours at ambient temperature. A heavy precipitate of dibenzylamine.HBr was filtered off. The filtrate was evaporated and crystallized first from MeOH and then from 2-PrOH. This yielded the product, 4'-(2-dibenzylaminoacetyl)methanesulfonanilide (XXVI) as a crystalline solid, 42.9 g, m.p. 131°-134°, whose thin layer chromatography analysis (silica, EtOAc/hexane) and NMR indicated a single compound with the structure indicated above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:31][C:32]([C@@H:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][N:35]2C(OC(C)(C)C)=O)=[O:33])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]3[CH:28]=[CH:27][N:26]([CH3:29])[C:25]3=[O:30])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[CH2:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43][C@@H:34]([C:32]([NH:31][C@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]3[CH:28]=[CH:27][N:26]([CH3:29])[C:25]3=[O:30])[CH2:14][CH2:13]2)=[O:11])=[O:33])[NH:35]1
Reactant: Cn1ccn(-c2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3C(=O)OC(C)(C)C)CC2)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ccn(-c2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3)CC2)c1=O
Yield: 59 %

Procedure:
The title compound was prepared according to the procedure described in Example 10 (Step c) from tert-butyl (3S)-3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-(4-[2-(3-methyl-2-oxo(4-imidazolinyl))phenyl]piperidyl)-2-oxoethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step c) (0.12 g, 0.17 mmol) and satd anhydrous HCl in EtOAc (50 mL). Recrystallization from 1:10 CH2Cl2:Kt2O provided the title compound (HCl salt) as a white solid (0.06 g). MP 178° C. (decomposed). MS (ESI, pos. ion) m/z: 598 (M+1). Calc'd for C34H36ClN5O3: 597.25. Anal. Calcd for C34H35ClN5O3.HCl.1.25H2O—C, 62.15; H, 6.06; N, 10.66; Cl, 10.79. Found: C, 62.20; H, 6.02; N, 10.68; Cl, 10.65.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)=O.CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(-c2ccnc(Cl)n2)s1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Clc1nccc(-c2ccc(CNc3ccccc3)s2)n1
Reaction time: 18 h
Yield: 59.4 %

Procedure:
[5-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carbaldehyde (100 mg, 0.446 mmol) was dissolved in 25% HOAc in DMA (4 mL) and was treated with aniline (61 uL, 0.669 mmol) for 2 h. MP-CNBH3 resin was added the reaction was shaken for 18 h. The reaction was filtered and rinsed with DMA and the solution was concentrated in vacuo. The crude material was purified by SiO2 chromatography using a gradient 0-100% hexanes/EtOAc to afford title compound (80 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]([Mg]Cl)=[CH2:12]>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH:11]=[CH2:12]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
2,4-Difluorobenzaldehyde (1.42 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0° C. Vinyl magnesium chloride (1M in tetrahydrofuran, 12 mL, 12 mmol) was added. The reaction was stirred for 30 minutes then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 10% ethyl acetate/isohexane, to give 1-(2,4-difluorophenyl)prop-2-en-1-ol (1.15 g). 1H NMR (500 MHz, CDCl3) δ 7.45-7.39 (1H, m), 6.90-6.86 (1H, m), 6.81-6.77 (1H, m), 6.07-6.00 (1H, m), 5.48 (1H, d, J=5.1 Hz), 5.35 (1H, d, J=17.1 Hz), 5.23-5.20 (1H, m), 2.06 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[C:30](O)=[O:31])=[CH:24][CH:23]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:30](=[O:31])[C:29]([CH2:28][C:25]3[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=3)=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c(Cc2ccc(O)cc2)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 61.2 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (196 mg) and 3-(4-hydroxyphenyl)pyruvic acid (162 mg) in ethanol (5 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(4-hydroxybenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (186 mg).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[CH2:28][OH:29].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][CH2:28][CH:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: OCC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1CO
Yield: 57.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 298 mg of 2,3-dihydro-1H-indol-2-ylmethanol and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 322 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 212 mg of 2-{2-[2-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink crystalline powder, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])=[CH:2]1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(OCc2ccoc2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccoc4)c(Cl)c3)c2cc1OC
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 6 hours, 4-amino-2-chlorophenyl 3-furylmethyl ether was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(3-furylmethoxy)anilino]-6,7-dimethoxyquinazoline hydrochloride salt in 79% yield, m.p. 244°-246° C.;
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([N:12]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13]3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:17][CH:14]1[CH2:15][CH2:16][N:12]([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:13]1
Reactant: CC1CCN(c2nccnc2C2CNC2)C1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 2-Azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride (44) (127 mg, 0.5 mmol, PREPARATION 13) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (rac)-2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline (127.65 mg, 0.37 mmol, yield 74%).