Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH:5]=[CH2:6])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:19])[S-:18])=[N:14][CH:15]=1.C([NH+](CC)CC)C>C(#N)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:18])[S:19][CH2:6][CH2:5][C:4](=[O:7])[C:2]([CH3:8])([CH3:3])[CH3:1])=[N:14][CH:15]=1
Reactant: C=CC(=O)C(C)(C)C
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A solution of 2,2-dimethylpent-4-en-3-one (30.0 g) in anhydrous acetonitrile (60 cc) is added, at a maximum of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (82.0 g) in anhydrous acetonitrile (400 cc). The reaction is allowed to proceed for 3 hours at between 5° and 20° C. The crystals which have appeared are filtered off and the filtrate is evaporated under reduced pressure (20 mm Hg) at 45° C. The resulting residue and the crystals which have been separated beforehand are dissolved in methylene chloride (750 cc). The organic solution is washed 4 times with distilled water (600 cc in total), dried over sodium sulphate and evaporated. The resulting product (98.0 g) is dissolved in chloroform (400 cc). The solution is chromatographed on a column of diameter 6.8 cm, containing silica (0.063-0.2 mm, 800 g). Elution is carried out first with chloroform (2.6 liters), this eluate being discarded, and then with chloroform (7.2 liters), this eluate being collected and evaporated to dryness. The resulting product (85.0 g) is purified by recrystallisation from acetonitrile (350 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (70.0 g) (structure determined by I.R. spectroscopy in petroleum jelly), which melts at 111° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)F
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1

Procedure:
4,4,4-Trifluoro-3-oxo-butyronitrile and phenylhydrazine were combined by the procedure of Example B22 to provide 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine. 1H-NMR (400 MHz, DMSO-d6) δ 7.59-7.50 (m, 4 H), 7.42 (m, 1 H), 5.78 (s, 1 H), 5.73 (br s, 2 H).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]>C(O)=O.Cl.C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=CC(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Product: C=CC(C)(C)C(=O)CCl
Yield: 85.9 %

Procedure:
57 g (0.256 mol) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene were warmed to 40° C. in a mixture of 250 ml of formic acid and 50 ml of concentrated hydrochloric acid for 1 hour. The mixture was then diluted with 400 ml of CH2Cl2 and ice, and was extracted 3 times by shaking with 2 N sodium hydroxide solution. After the methylene chloride phase had been dried over Na2SO4, the solvent was stripped off in a rotary evaporator. There remained 36 g (96%) of crude product. 32.2 g (0.22 mol, 86%) of 1-chloro-3,3-dimethyl-pent-4-en-2-one were obtained by distillation (b.p. 81°-84° C./24 mm Hg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[CH3:22]/[C:23](/[CH:31]=[O:32])=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H][H]>>[CH3:22]/[C:23](/[CH2:31][OH:32])=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C/C(C=O)=C/c1ccccc1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C/C(=C\c1ccccc1)CO
Yield: 93.7 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an ethanolic solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol) and α-methyl cinnamic aldehyde (1.26 mL, 9 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (>99%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 1.25 g of the α-methyl cinnamic alcohol was obtained (yield: 94%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1)[CH2:7][CH2:8][CH3:9].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>ClC(Cl)C>[CH2:6]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[C:14]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Temperature: 23 °C
Reaction time: 24 h

Procedure:
59.8 ml (0.50 mole) of tin tetrachloride are added gradually to a solution of 44.5 g (0.2 mole) of 2-n-butyl 5-nitro benzofuran and 44.3 g (0.26 mole) of anisoyl chloride in 308 ml of dichloroethane. The temperature is maintained at 23° C. and stirring is continued for 24 hours. The mixture is poured onto 770 ml of ice-water and extracted 3 times with 150 ml of dichloroethane. The solution is washed with water, 5% sodium hydrogen carbonate solution and again with water. It is evaporated to dryness and the product thus obtained crystallizes rapidly [purity on high performance liquid chromatography (HPLC): 91.69%]. It is recrystallized from 250 ml of isopropanol and 59 g of 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].COCCO.Cl>C(O)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:18]3[CH2:19][CH2:20][CH2:21][O:17]3)=[O:23])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 70 °C
Yield: 93.1 %

Procedure:
A slurry of 60 grams (0.25 mol) of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 55.3 g (0.3 tool) of 1-(2-tetrahydrofuroyl)piperazine and 175 grams of 2-methoxyethanol was heated, under a nitrogen atmosphere with mechanical stirring, to 120°-123° C. for eight hours. The slurry was then cooled to 70° C. and 140 ml of 3A 200 proof ethanol was added. The resulting mixture was heated to 60°-70° C. for one hour and then cooled to 0°-5° C. To the cooled solution was added 2.5 g of concentrated aqueous hydrochloric acid in 12 ml of 3A 200 proof ethanol. This mixture was kept at -5°-5° C. for one and one-half hours after which the precipitated solid was collected by filtration and washed with 50 ml of cold 3A 200 proof ethanol to yield 98.7 g (0.233 tool, 93%) of anhydrous 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride of a previously unknown crystalline modification.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(C=O)c1OCc1ccccc1
Yield: 93 %

Procedure:
A mixture of 196.0 g (1.30 mole) of o-vanillin (Aldrich), 200 g of benzyl bromide (Aldrich), 500 g of anhydrous potassium carbonate and 1,500 mL of absolute ethanol is heated, with stirring, at reflux for 6 hours. After cooling, the supernatant is decanted and the remainder is filtered. The combined filtrate and supernatant is concentrated at reduced pressure to remove solvent. The remaining oil is extracted into 1 L of ether. The ether solution is washed with 500 mL of water, 600 mL of 1% potassium hydroxide solution, and 500 mL of water and then dried (potassium carbonate) and concentrated to give 263.4 g (84% yield) of product; mp 41°-43° C. Reported mp, 43° C. (Chem. Abstr. 62:16110a).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:13]1([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-Nitrophenol (5.0 g, 35.9 mmol) was added to a suspension of (bromomethyl)cyclopropane (10.7 g, 79.07 mmol) and K2CO3 (19.9 g, 143.76 mmol) in DMF (80 mL), and the reaction was stirred at 40° C. overnight. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc/PE) to give 6.77 g (98%) of the title compound as a colorless oil. [M+H] Calc'd for C10H11NO3, 194. Found, 194.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26](Cl)=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C>C(O)C>[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]([NH:2][CH:3]4[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]4)=[C:21]3[CH:20]=[CH:19]2)(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCC(O)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
A mixture of 3-Amino-cyclopentanol hydrochloride (0.9 g, 5.9 mmol), 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 5.9 mmol) and diisopropylethylamine (2.3 g, 17.7 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 hours. The reaction mixture was purified by column chromatography (Hexanes/ethyl acetate=3:1) to give 2.6 g (76%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol; 1H NMR (400 MHz, CDCl3) δ: 9.56 (s, 1H), 9.54 (s, 1H), 8.19-8.16 (m, 2H), 7.62-7.56 (m, 4H), 6.82-6.81 (m, 1H), 4.56-4.50 (m, 2H), 2.25-1.96 (m, 6H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[Na+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:3][CH2:2][CH2:1][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCc1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethylene glycol (742.5 g, 11.96 mol) was added to a solution of sodium hydroxide pellets (475.2 g, 11.88 mol) in 450 ml of water kept at 80° C. Benzyl chloride (302.8 g, 2.39 mol) was then added at 65° C., and the resulting suspension was vigorously stirred at 120° C. overnight. After cooling to room temperature, the mixture was poured into ice-water and extracted five times with diethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The remaining residue was then distilled under vacuum and the relevant fractions (bp. 95-125° C. at 0.1-1 mbar) collected.
Reaction SMILES: [I:1][C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[I:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: OCc1cc2c(cc1I)OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc2c(cc1I)OCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
(6-Iodobenzo[d][1,3]dioxol-5-yl)methanol (2.7 g, 9.7 mmol) in dry CH2Cl2 was added dropwise to PCC (3.1 g, 14.6 mmol) in dry CH2Cl2 at 0° C. under N2 atmosphere. The mixture was stirred at room temperature for 20 h. After reaction, the crude product was purified by column chromatography on silica gel (petroleum ether) to obtain 6-iodobenzo[d][1,3]dioxole-5-carbaldehyde (2 g, 77%) as white solid. LCMS: 277[M+1]+; 1H NMR (DMSO-d6) δ 6.20 (s, 2H), 7.28 (s, 1H), 7.61 (s, 1H), 9.79 (s, 1H).
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].C(N(CC)CC)C.Cl[C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:5][CH2:1][C@H:2]([OH:4])[CH3:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of (2R)-1,2-propanediol (1.9 mL) in toluene (20 mL) was added triethylamine (8.3 mL) and 4-dimethylaminopyridine (32 mg). The mixture was ice-cooled and 1,1′,1″-(chloromethylidyne)tris-benzene (6.6 g) was added and the mixture stirred at ambient temperature for 20 h. The reaction mixture was diluted with toluene then extracted with ammonium chloride solution (×2), then brine (×1) and the organic layer was dried (MgSO4), filtered and evaporated. The resulting oil was triturated with iso-hexane to give subtitle compound as a white solid. Yield: 4 g
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C

Procedure:
26 g of 3-methyl-2-thiophenecarboxaldehyde was dissolved in 100 ml of chloroform and the solution was stirred by cooling with ice 11 ml of bromine was added dropwise thereto. The temperature was elevated to room temperature and the mixture was stirred overnight. About 1 l of ethyl acetate was added thereto and the mixture was washed with water, then with a saturated aqueous sodium hydrogencarbonate solution and finally with a saturated aqueous common salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 46.8 g of 5-bromo-3-methyl-2-thiophenecarboxaldehyde in the form of a dark brown solid, which was subjected to the subsequent reaction without purification.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Br)(Br)([Br:14])=O>ClC(Cl)C>[Br:14][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Solvent: CC(Cl)Cl
Product: Cc1cc(Br)ncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 2-hydroxy-4-methyl-5-nitropyridine (1 g, 6.5 mmol) in dichloroethane (10 mL) was added a solution of phosphorus oxybromide (2.8 g, 9.7 mmol) in dichloroethane (10 mL). The reaction mixture was heated under reflux for 4 h, then cooled to rt and quenched with water (40 mL). The layers were separated and the aqueous layer extracted into dichloromethane (2×3 mL). The combined organics were dried (MgSO4), concentrated in vacuo and chromatographed on silica gel eluting with dichloromethane to give the title compound as a pale yellow solid. δH (CDCl3): 2.63 (3H, s), 7.52 (1H, s), 8.96 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[Sn:13](Cl)([CH3:16])([CH3:15])[CH3:14].N#N>C1COCC1>[CH3:14][Sn:13]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: N#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To anhydrous THF (100 ml) containing 3-bromo-pyridine (3.29 g, 20.82 mmol), were added 1.2 eq of iPrMgCl (12.49 ml, 2M in THF) and the resulting mixture was stirred for 2 hours under N2 (10° C.). Subsequently 1.2 eq of (CH3)3SnCl were added and the reaction mixture was stirred for 18 hours at room temperature (under N2). The reaction mixture was quenched with a saturated NH4Cl solution, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-trimethylstannanyl-pyridine (71) (3.32 g, 66%). LCMS (method A): Rt: 2.09 min, ([M+H]+=242). 1H-NMR (400 MHz, CDCl3): δ 8.62 (bs, 1H), 8.52 (dd, J=5 Hz, 2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.25-7.21 (m, 1H), 0.33 (s, 9H), with Sn satellites at 0.41 and 0.27.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC/C=C/c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) in DCM (300 ml) under nitrogen and cooled to −78° C. was added dropwise DIBAL-H (240 ml, 1M in DCM, 240 mmol) in about 20 minutes. The mixture was stirred at −78° C. for 2 hours. Then, the dry ice bath was removed. The reaction was diluted with DCM (500 mL), quenched with HCl (1N), and partitioned. The combined organic phases were washed with H2O, dried and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 1.43 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (d, J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCI—NH3) m/z 214 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>ClCCl>[C:12]([Si:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
4-Iodophenol (1.0 g, 4.55 mmol) was dissolved in dichloromethane (5 mL). tert-Butyldimethylsilyl chloride (0.685 g, 4.55 mmol) and imidazole (0.309 g, 4.55 mmol) were added. The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between water (30 mL) and dichloromethane (30 mL). The organic layer was removed and the aqueous layer was extracted with dichloromethane (30 mL). The organic layers were combined, dried and concentrated, and the residue was purified by chromatography (0-10% EtOAc/hexanes) to give the title compound as a light yellow oil (1.45 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH:12]=[CH:13][O:14]CC)[CH:6]=2.C(O)=O>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=[O:14])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC=Cc1cnc2cc(Br)cnc2c1
Solvent: O=CO
Solvent: ClCCCl
Product: O=CCc1cnc2cc(Br)cnc2c1

Procedure:
1,5-Naphthyridines of formula (53), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 7. 3,7-Dibromo-[1,5]naphthyridine, prepared as described by W. W. Paudler, J. Org. Chem., 33:1384 (1968), can be treated with (2-ethoxyvinyl)tributylstannane, a halide source, such as, but not limited to, tetraethylammonium chloride, and a palladium source, such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N,N-dimethylformamide with heat (about 50° C. to about 150° C.) to provide 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine. 3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with an acid, such as, but not limited to, formic acid at about 0° C. to about 60° C. in a solvent, such as, but not limited to, 1,2-dichloroethane to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively, 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as, but not limited to, tetrahydrofuran can be treated with an aqueous acid, such as, but not limited to, hydrochloric acid at about 0° C. to about 60° C. to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. (7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with an amine of formula (5) under reductive amination conditions, such as, but not limited to, sodium triacetoxyborohydride and an acid, such as, but not limited to, acetic acid in a solvent, such as, but not limited to, 1,2-dichloroethane at about 0° C. to about 50° C. to povide amines of formula (52). Amines of formula (52) can be treated with boronic acids of formula (7), a palladium source, such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0), a ligand, such as, but not limited to, tri(tert-butyl)phosphine, and a base, such as, but not limited to, potassium fluoride in a solvent, such as, but not limited to, tetrahydrofuran at about 20° C. to about 80° C. to provide 1,5-naphthyridines of formula (53).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O)C.[OH-].[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 91.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), ethanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C. A 20% aqueous solution of sodium hydroxide was added to the mixture so as to adjust the pH of the mixture at 8.0-8.5. Twenty-seven hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 67.6 g of p-cyanobenzoic acid (yield 92%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH to 3.1. The mixture was heated again to 82° C. to dissolve. The resultant mixture was cooled for crystallization, to thereby obtain 64.2 g of p-cyanobenzoic acid crystal (purity 95.0%, yield 83%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12].O>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(F)c(Br)c1
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (0.075 g) was added to a stirred solution of 3-bromo-4-fluorobenzaldehyde (1.2 g) in dry tetrahydrofuran (20 cm3), the temperature being maintained below 5° C. by external cooling. The temperature of the reaction mixture was then allowed to rise to the ambient value (ca 20° C.) and the mixture was stirred for 2 hours; GLC analysis of a withdrawn sample indicated 82% conversion at this time, and further lithium aluminium hydride (0.025 g) was therefore added to the mixture. After a further 1.5 hours GLC analysis indicated that the reaction was complete. The mixture aas poured into water (20 cm3) and the products extracted into diethyl ether (3×20 cm3). The combined ethereal extracts were washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave the title compound in high purity.