Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14][N:26]=[N+:27]=[N-:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)(C2CCCCC2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])(C2CCCCC2)CC1
Temperature: 100 °C
Yield: 76 %

Procedure:
To a solution of 4-cyclohexyl-4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 4, (2.42 g, 6.73 mmol) in DMF (25 mL) is added sodium azide (1.32 g, 20.2 mmol) and the mixture is heated and stirred at 100° C. over night. The reaction is cooled and then quenched with water. The resulting solution is extracted with EtOAc (30 mL), dried, filtered and concentrated in vacuo to afford the crude product as a brown oil which is purified via chromatography on silica gel eluting with hexane/EtOAc 3:1 to afford the desired product in 76% yield (1.91 g) as a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([OH:8])=[O:7].[CH2:21](O)[CH3:22]>>[CH2:21]([O:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=[O:8])[CH3:22]
Reactant: CCO
Reactant: O=C(O)CCCn1ccc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCCn1ccc2ccccc21

Procedure:
Phosphorus oxychloride (10 ml) was added dropwise with cooling to a stirred solution of 1-(3-carboxypropyl)indole (100 g) in ethanol (750 ml). The solution was heated under reflux for 8 hours and then evaporated. The residue was distilled to give 1-(3-ethoxycarbonylpropyl)indole (95.0 g), b.p. 164°-170° C./2 m.m.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NC1CC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NC1CC(CON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 6a, starting from 1.59 g (0.0079 mol) of 3-(N-BOC-amino)-cyclobutanemethanol (EP 0 366 059 A2), 1.29 g (0.0079 mol) of N-hydroxyphthalimide, 2.07 g (0.0079 mol) of triphenylphosphine and 1.39 ml (0.0083 mol) of diethyl azodicarboxylate (93%), the title compound is obtained, m.p. 108°-109° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[C:16]([Cl:23])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:17]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:23])[CH2:13][CH2:12][CH2:11]3)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: OCC(O)Cc1c(Cl)cc2c(c1OCc1ccccc1)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2c(Cl)cc3c(c2OCc2ccccc2)CCC3)cc1
Yield: 77 %

Procedure:
Treatment of (±)-3-[4-(benzyloxy)-6-chloro-2,3-dihydro-1H-inden-5-yl]propane-1,2-diol (5.60 g, 0.0168 mol) with p-toluenesulfonyl chloride (3.70 g, 0.0194 mol) in pyridine (200 mL) generally according to the procedure described for Intermediate 18 provided 6.30 g (77%) of (±)-3-[4-(benzyloxy)-6-chloro-2,3-dihydro-1H-inden-5-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a light yellow oil. 1H NMR (DMSO-d6) 8H 7.65(d, 2H); 7.40(m, 7H); 7.05(s, 1H); 5.25(s, 1H); 4.90(s, 2H); 3.80(m, 3H); 2.90(m, 2H); 2.80(m, 3H); 2.65(dd, 1H); 2.40(s, 3H); 2.00(m, 2H).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:5](N)=[N:6][CH:7]=[CH:8][C:9]=1[CH3:10].N([O-])=O.[Na+]>Br.O>[Br:1][C:5]1[C:4]([Br:3])=[C:9]([CH3:10])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccnc(N)c1Br
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(Br)c1Br
Temperature: 10 °C
Yield: 46.5 %

Procedure:
Bromine (0.35 mL, 6.8 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridin-2-ylamine (0.44 g, 2.4 mmol) in 48% HBr (3 mL) at −10° C. to give an orange slurry. After 5 minutes NaNO2 (0.47 g, 6.8 mmol), dissolved in water (1.5 mL), was added dropwise over 5 minutes. The dark brown mixture was slowly warmed to 10° C. over 3.5 h and then cooled to 0° C. and quenched with 10N NaOH until pH˜12. The resulting orange slurry was extracted with CH2Cl2 (3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an orange/brown solid. Purification by column chromatography on silica gel (Hexanes:Et2O, 7:3, v/v) yielded 2,3-dibromo-4-methyl-pyridine (0.28 g, 47%) as a pale yellow solid. 1H NMR (CDCl3) δ 2.48 (s, 3H), 7.11 (d, 1H, J=6.0 Hz), 8.16 (d, 1H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32](I)([CH3:34])[CH3:33]>O>[CH:32]([O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2)([CH3:34])[CH3:33]
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To a mixture of 0.26 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g of potassium carbonate and 3 ml of DMF, 0.17 g of isopropyl iodide was added at room temperature and stirred while heating at 60° C. for 1.5 hours. To the reaction solution, 38 mg of potassium carbonate and 47 mg of isopropyl iodide were added, and the reaction solution was stirred while heating at 60° C. for two hours. The reaction solution was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.16 g of 2-(3-isopropoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 160”).
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18](O)[CH2:19][O:20]C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3][CH:2]=1.CCCCCC.CN(C)[CH:57]=[O:58]>O1CCCC1>[C:1]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([O:58][CH3:57])[CH2:19][OH:20])=[CH:3][CH:2]=1
Reactant: COc1ccc(C(OCC(O)COCCCCCCCCOc2ccc(-c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(CO)COCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A solution of 7.6 g of 1-[[8-([1,1'-biphenyl]-4-yloxy)octyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 20 ml of dimethylformamide and 20 ml of tetrahydrofuran was added dropwise to a solution of 849 mg of hexane washed 50% sodium hydride in 50 ml of dimethylformamide containing 5.02 g of methyl iodide over 35 minutes under argon. The mixture was stirred overnight then ice was cautiously added followed by 300 ml of iced water. This mixture was extracted three times with ether, the extracts combined, washed with water, dried and evaporated. The residue was taken up in 65 ml of chloroform and 130 ml of methanol, heated to boiling, 8 g of Amberlite® IR-4B ion exchange resin added, stirred for 2 hours, filtered and evaporated. The residue was purified by chromatography, giving 1.27 g of 3-[[8-([1,1'-biphenyl]-4-yloxy]octyl]oxy]-2-methoxy- 1-propanol.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CN1CCCC1=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCC(C)O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 145 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of N-methylpyrrolidone. The stirred mixture is heated to 145° C. and held for one hour, then cooled to about room temperature. Then 150 ml of 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried. There is obtained 10.7 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 82.5% pure, or a 57.0% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[CH3:10][N:11]([CH3:17])[CH2:12][CH2:13][C:14](O)=[O:15].C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH3:17])[CH3:10])[CH:3]=[N:4][CH:5]=1
Reactant: CN(C)CCC(=O)O
Reactant: Nc1cncc(Br)c1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CN(C)CCC(=O)Nc1cncc(Br)c1
Temperature: 50 °C

Procedure:
To a solution of 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 11.2 mmol, 2.00 g) and 3-dimethylaminopropionic acid hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1 eq, 11.2 mmol, 1.74 g) in DCM (50 ml), tributylamine (3.6 eq, 40.4 mmol, 9.8 ml) and 2-chloro-1-methylpyridinium iodide (1.2 eq, 13.5 mmol, 3.54 g) are added. The resulting mixture is heated at 50° C. for 4 h, then the solvents are removed in vacuo, aqueous NaOH solution (1 M) is added, and the mixture is extracted with DCM. The organic layer is dried with MgSO4, filtered, and the solvent is removed in vacuo. Purification by column chromatography (DCM/MeOH) yields the title compound; [M+H]+=273.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:14].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:6]2[N:7]=[C:8]([S:11][CH3:12])[S:9][C:10]=2[C:2]([N:1]=[C:16]=[O:15])=[C:3]([F:14])[CH:4]=1
Reactant: CSc1nc2c(Cl)cc(F)c(N)c2s1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1nc2c(Cl)cc(F)c(N=C=O)c2s1

Procedure:
First, 4-chloro-6-fluoro-7-isocyanato-2-(methylthio)benzothiazole was prepared by refluxing a solution of 7 g (28 mmol) of 7-amino-4-chloro-6-fluoro-2-(methylthio)benzothiazole and 55 g (0.28 mol) of diphosgene (200 ml of toluene for 7 hours, then adding 20 g (0.1 mol) of phosgene, refluxing for a further 8 hours and finally evaporating down.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:17]=[CH:18][CH2:19][O:20]CC1C=CC=CC=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:17]=[CH:18][CH2:19][OH:20])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C=CCOCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C=CCO)C(=O)OC(C)(C)C

Procedure:
Mix 2-(N-t-butyloxycarbonylamino)-5-(O-benzyloxy)-3-pentenoic acid, t-butyl ester (2.0 g, 5.3 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 mL). Hydrogenate at room temperature at atmospheric pressure. Filter and evaporate the filtrate in vacuo to give 2-(N-t-butyloxycarbonylamino)-5-hydroxy-3-pentenoic acid, t-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN2CCOCC2)c(C=O)c1
Temperature: 70 °C

Procedure:
A stirred solution of 25 g of 2-hydroxy-5-methoxybenzaldehyde in 125 ml. of dimethylformamide is treated portionwise with 8.2 g of 50% sodium hydride (oil dispersion). The temperature is kept below 35° C. by means of an ice-water bath. When the addition is complete, the mixture is warmed to 70° C. and cooled to 25° C. This is followed by the addition of a solution of 36 g. of N-(3-chloropropyl)morpholine in 65 ml. of toluene. The mixture is stirred and heated at 100°-105° C. for 4 hours, cooled, poured into 300 ml. of ice-water and extracted with three 150 ml. portions of ether. The combined ether layers are then extracted with 40 ml. of cold 1:1 hydrochloric acid, followed by 20 ml of water. The aqueous phases are combined, layered over with 150 ml of ether, stirred and basified with 40 g. of potassium carbonate. The layers are separated and the aqueous phase is extracted with three 100 ml portions of ether. The combined ether layers are dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is distilled to give 34 g. of the title compound, boiling point 180°-185° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[CH:10][CH2:11][C:3]=12.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:12][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]=2[CH2:11][CH:10]=[N:9]1
Reactant: CN1N=CCc2c(Cl)ncnc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1N=CCc2c(-c3ccccc3)ncnc21
Temperature: 100 °C
Yield: 91.9 %

Procedure:
The 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310 mg), phenyl boronic acid (208 mg) and potassium carbonate (235 mg) were dissolved in toluene (10 mL) and water (1.0 mL). The reaction mixture was degassed with nitrogen for 30 minutes and Pd(PPh3)4 (98 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 1 hour in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by column chromatography using MeOH/CHCl3 (1.0:9.0) as eluent to afford 1-methyl-5-phenyl-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) as off white solid. 1H NMR (DMSO-d6): δ 3.41 (s, 3H), 3.52-3.53 (d, 2H), 6.86 (t, 1H), 7.47-7.49 (m, 3H), 7.56-7.60 (m, 2H), 8.66 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH3:25][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:15]([NH:14][C:10]1[C:6]2[O:7][C:8]([CH3:9])=[C:4]([C:1]([OH:3])([CH3:25])[CH3:2])[C:5]=2[CH:13]=[CH:12][CH:11]=1)=[O:24]
Reactant: CC(=O)c1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-acetyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (100 mg) in tetrahydrofuran (3 ml) was added a 1M solution of methylmagnesium bromide in tetrahydrofuran (0.7 ml) dropwise with ice cooling. The solution was stirred at ambient temperature for 2 hours and to the solution was added aqueous saturated ammonium chloride. Then, the mixture was poured into water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by colimn chromatography on silica gel and the obtained oil was crystallized from a mixture of diisopropyl ether and hexane to give 7-(2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (75 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:32]([N:36]=[C:37]=[O:38])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37]([O:31][C:28]1[CH:29]=[CH:30][C:2]([NH:1][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])=[C:3]([CH:27]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13]1)=[O:5])=[O:38])[CH2:33][CH2:34][CH3:35]
Reactant: Nc1ccc(O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1ccc(OC(=O)NCCCC)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
{2-amino-5-hydroxy-N-[(1-diphenylmethylpiperidin-4-yl)methyl]-benzamide and n-butyliso-cyanate}: mp 197°-199° C.; 1H NMR(CDCl3)ppm: 0.90 (3H, t), 1.20-1.90 (11H, m), 2.88 (2H, m), 3.18 (2H, td), 3.25 (2H, dd), 4.23 (1H, s), 5.31 (1H, bs), 6.88 (1H, dd), 6.97 (1H, d), 7.10-741 (11H, m), 7.95 (1H, d), 8.66 (1H, s), 9.40 (1H, s); and,
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH:13][CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:21][CH:20]([CH3:22])[CH:14]([NH:13][C:11]1[O:12][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][N:10]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(NC(=O)NNC(=O)c1ccccc1)C(C)C
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Nc1nnc(-c2ccccc2)o1)C(C)C
Temperature: 77.5 °C

Procedure:
To a solution of crude ethyl 2-(2-benzoylhydrazinecarboxamido)-3-methylbutanoate (assumed 5 mmol) in DCE (10 ml) was added POCl3 (1.5 g, 10 mmol). Upon completion of addition, the reaction was heated at 75-80° C. overnight. After this time, the excess solvent and POCl3 were removed in vacuo. The resulting remains were dissolved in EtOAc (75 ml) and washed sequentially with sat. aqueous NaHCO3 (2×25 mL) solution and sat. aqueous NaCl (25 mL) solution and dried over MgSO4. The solvent was removed in vacuo to give ethyl 3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoate in greater than 90% purity by LCMS; m/z (290, M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[C:3]([CH3:11])=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Cc1cc2nccn2nc1Cl
Solvent: CC(=O)O
Product: Cc1cc2ncc(Br)n2nc1Cl
Yield: 69.8 %

Procedure:
The 6-chloro-7-methylimidazo[1,2-b]pyridazine 8 (0.230 g, 1.372 mmol) was taken in glacial acetic acid (10 ml) and bromine (0.070 ml, 1.372 mmol) was added slowly at room temperature. After 20 mins the solvents were evaporated the obtained brown solid was washed with ether (3×15 ml) and dried under air to furnish compound 9 (0.236 g, yield 69.8%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH2:21][CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]4=[O:20])[C:3]=3[CH2:21][CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-3-ethyl-5,7-difluoroquinolin-2-yl)piperidin-2-one (40.0 mg, 0.120 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)-amino)-3-ethyl-5,7-difluoro-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.96 (1H, d, J=11.9 Hz), 7.60 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.0 Hz), 6.90-7.07 (1H, m), 6.71 (1H, br. s.), 4.38 (1H, br. s.), 3.85-4.03 (4H, m), 3.71-3.84 (4H, m), 3.58 (1H, d, J=11.0 Hz), 3.34 (2H, ddd, J=11.9, 6.1, 2.9 Hz), 3.08-3.19 (3H, m), 2.92-3.07 (2H, m), 2.43-2.62 (3H, m), 1.92-2.26 (6H, m), 0.97-1.11 (3H, m). Mass Spectrum (ESI) m/e=554.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O.C(#N)C>[C:27]1(=[O:36])[N:14]([CH:12]([CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:13])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(CC(C)N)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(C)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(3,4-dimethoxyphenyl)-2-aminopropane (1.95 grams, 10.0 mmol) and sodium carbonate (1.06 grams, 10.0 mmol) in 50 milliliters of water was added N-carbethoxyphthalimide (2.19 grams, 10.0 mmol). After 10 minutes the reaction mixture was diluted with 40 milliliters of acetonitrile and the mixture stirred for 40 minutes The reaction solution was partially concentrated in vacuo to remove the acetonitrile. The resulting mixture of an oil and aqueous layer was extracted with methylene chloride (25 milliliters). The organic extract was dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by flash chromatography to afford 1.73 grams (53%) of product as a thick oil which slowly solidified to a white wax: 1H NMR (dmso-d6, 250 MHz) δ7.7 (m, 4 H, Ar), 6.7 (m, 3 H, Ar), 4.63 (m, 1 H, CH), 3.79 (s, 3 H, OMe), 3.73 (s, 3 H, OMe), 3.28 (dd, 1 H, J =13.8, 9.8 Hz), 3.03 (dd, J=13.8, 6.5 Hz, 1 H), 1.54 (d, J=6.9 Hz, 3 H); 13C NMR (dmso-d6) δ168.4, 148.6, 147.4, 133.7, 131.8, 130.9, 122.9, 120.9, 111.1, 55.7, 55.6, 48.6, 39.3, 18.3. Anal. Calcd for C19H19NO2. Theoretical C, 70.14; H, 5.89; N, 4.30. Found C, 70.08; H, 5.83; N, 4.30.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([Cl:22])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)COc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 8.3 g (0.0298 mol) of 4-(4-chlorophenoxy)-phenoxy-acetic acid (CRL 40 333) prepared as indicated in Example 19 and of 10.8 ml (0.1500 mol) of thionyl chloride is heated to the reflux temperature for 30 minutes. After having taken up the reaction mixture in benzene and evaporated the solution to dryness under reduced pressure, 8.7 g of a beige powder are obtained.