Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[Mg]Br.[O:16]1[C@:20]([CH3:37])([CH2:21][CH2:22][CH2:23][C@H:24]([CH3:36])[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:17]1[CH:18]=[O:19].O>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:18]([OH:19])[C@H:17]1[O:16][C@:20]1([CH3:37])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:36])[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34]
Reactant: COc1c(C)c(C)c(OC)c([Mg]Br)c1C
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@]1(C)O[C@H]1C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(O)[C@H]2O[C@]2(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
1 mmol of 2,5-dimethoxy-3,4,6-trimethylphenylmagnesium bromide in 2 ml of tetrahydrofuran was added dropwise at 0° C. while stirring to a solution of 300 mg (0.97 mmol) of (2R,3R,7R,11R)-2,3-epoxy-3,7,11,15-tetramethylhexadecanal in 10 ml of tetrahydrofuran. After completion of the dropwise addition, the mixture was stirred at room temperature for a further 3 hours. 20 ml of water weree then added and the mixture was extracted three times with 20 ml of ether each time. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. The thus-obtained crude produce (502 mg) was chromatographed on silica gel with toluene/ethyl acetate (2:1 parts by volume) and there were obtained 448 mg(94%) of (1RS,2R,3R,7R, 11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-3,7,11,15-tetramethylhexadecanol, [α]D20 =-0.66° (c=1.51% in chloroform).
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH2:13][CH2:14][CH:15]([OH:22])[CH2:16][C:17]=3[C:18]2=[O:21])=[CH:9][CH:8]=1.[OH-].[Na+].COS(OC)(=O)=O>O.C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH2:13][CH2:14][CH:15]([O:22][CH3:2])[CH2:16][C:17]=3[C:18]2=[O:21])=[CH:9][CH:8]=1
Reactant: O=c1c2c(oc3ccc(Br)cc13)CCC(O)C2
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC1CCc2oc3ccc(Br)cc3c(=O)c2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To 100 ml of an anhydrous tetrahydrofuran solution containing 5.9 g of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-xanthone obtained in Example 67 was added 1.1 g of sodium hydroxide (as 55% dispersed in an oil). The mixture was stirred at 50° C. for 1 hour to which was then added dropwise 3.3 g of dimethylsulfate. The resulting mixture was agitated at 60° C. for 1.5 hours. After completion of the reaction, the solvent was removed by distillation to give a residue to which were added chloroform and water. The chloroform phase was collected and washed with water, and then dried with anhydrous sodium sulfate and purified by chromatography on silica gel. The crude crystals thus obtained were recrystallized from benzene/hexane to obtain 3.87 g (yield: 62.6%) of 7-bromo-2-methoxy-1,2,3,4-tetrahydro-9-xanthone as colorless needlelike crystals having a melting point of 139° to 142° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:23])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][N:14]1[CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2CN1CCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (150 mg, 1 mmole) and 2-[2-(bromo)ethyl]isoindolin-1-one (240 mg, 1 mmole) in ethanol (15 ml) was added triethylamine (0.21 ml, 1.5 mmoles) and the mixture Was stirred at room temperature for 12 hours and heated at reflux for 2 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (15:1)] to obtain 238 mg of the desired product (77.0%, light brown solid).
Reaction SMILES: [BH4-].[K+].[CH:3]([O:16][C:17]([C:19]1[N:24]2[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:23]2[S:22][CH2:21][C:20]=1N1CCCC1)=[O:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C)C=O.C(Cl)Cl.C(O)C.C(O)(=O)C>[CH:3]([O:16][C:17]([C:19]1[N:24]2[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:23]2[S:22][CH2:21][CH:20]=1)=[O:18])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCCC3)CS[C@H]12
Agent: [BH4-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
While cooling with ice, a solution of 5.4 g (100 mmols) of potassium borohydride in 50 ml of dimethyl formamide is added over 1 hour to a solution of 11.4 g (20 mmols) of 7β-phenoxyacetylamino-3-pyrrolidino-3-cephem-4-carboxylic acid benzhydryl ester in 50 ml of methylene chloride, 50 ml of ethanol and 50 ml of glacial acetic acid. The mixture is then stirred for 36 hours at room temperature, concentrated to half its volume, diluted with ice-water, and extracted several times with methylene chloride. The solvent is then removed by vacuum distillation, affording 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:19])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([NH:14]3)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.C(N(C(C)C)CC)(C)C.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:19])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2CC1CC1
Yield: 32 %

Procedure:
To a stirred solution of 2.2 g of 10-chloro-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 40 ml of dimethylformamide was added 3.2 ml of diisopropylethyl amine and 1.07 ml of cyclopropylmethyl bromide, under nitrogen. The reaction mixture was warmed in an oil bath maintained at 70°-77° C. Additional cyclopropylmethyl bromide (0.16 ml) was added, warming continued for a total of 3 hr, and the solution was poured into dilute aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/0-5% methanol/ethyl acetate) followed by recrystallization from ether/dichloromethane/pentane to afford 0.97 g (32%) of product. The product was combined with products from two other reactions. The combined material was recrystallized from dichloromethane and the sublimed (175°-180° C., about 0.2 mm) to give the analytical sample, mp 187°-190° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(N(CC)CC)C.CN(C)C(=O)C>O>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N+:12]([O-:14])=[O:13])[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1NCCCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
A mixture of 43 parts of N-(3-chloropropyl)-2-nitrobenzenamine 47.8 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 30.3 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylacetamide is stirred and heated for 6 hours at 100° C. The reaction mixture is cooled and poured onto 1500 parts of water. The precipitated product is filtered off, washed with water and with 2,2'-oxybispropane and dried, yielding 64 parts (78.3%) of 5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one; mp. 220° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7].O.ClCCl>CCOC(C)=O.C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:2](=[O:1])[CH3:3])=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
To a suspension of sodium ethoxide (4.49 g, 66 mmol) in EtOAc (10 mL) that was cooled to −5° C. was added a solution of 4-bromoacetophenone (11.94 g, 60 mmol) in EtOAc (10 mL) and THF (10 mL). The mixture was stirred at 0° C. for 4 hours before warming to ambient temperature and stirring for 48 hours. Water (20 mL) and dichloromethane (40 mL) were added and a white precipitate was filtered from the mixture. To the solid was added 2N HCl, with vigorous stirring, to pH 1. EtOAc (100 mL) was added and separated, and the water was washed with EtOAc (2×100 mL). The organic portions were combined, dried (Na2SO4) and concentrated in vacuo to yield the desired compound as a pale yellow, crystalline solid (11.09 g, 76%); 1H-NMR (CDCl3): 2.13 (s, 3H, CH3), 6.07 (s, 1H, ═CH), 7.52 (d, 2H, J=8.7 Hz, Ar-2, Ar-6), 7.67 (d, 2H, J=8.7 Hz, Ar-3, Ar-5).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:45]=[CH:44][C:43]=1[C:56](=[O:58])[CH3:57])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:45]=[CH:44][C:43]=1[C:56](=[O:58])[CH2:57][Br:1])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Phenyltrimethylammonium tribromide (5.6 g, 0.015 mol) was added portionwise to a stirred solution of 1-(2,4-Bis-benzyloxyphenyl)-ethanone (5.0 g, 0.015 mol) in tetrahydrofuran (50 ml) and the mixture was stirred for 2 h. The mixture was partitioned between water (50 ml) and diethyl ether (2×50 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give 1-(2,4-Bis-benzyloxyphenyl)-2-bromo-ethanone as a beige solid which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C[Si](C#N)(C)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[C:19]([CH3:28])[C:18]=1[CH3:29].CO>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24]([NH:1][C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])(=[O:25])=[O:26])=[C:19]([CH3:28])[C:18]=1[CH3:29]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: C[Si](C)(C)C#N
Solvent: CO
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)c(C)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of D-threonine (7.87 g, 66.1 mmol) in acetonitrile (100 mL) was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resulting solution was heated to 80° C. After 1 h, 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (17.3 g, 69.4 mmol) was added and the heating was continued. After 12 h, the reaction mixture was cooled to room temperature. Methanol (15 mL) was added, and the organics were removed in vacuo. The residue was diluted with diethyl ether (300 mL) and after cooling the reaction mixture to 0° C., the pH was adjusted to 8 with 6 N aqueous sodium hydroxide solution. The organic layer was collected and the aqueous layer was extracted with diethyl ether. The aqueous layer was adjusted to pH 4 and again extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyric acid (22 g) as a brown foam which was used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([CH2:10][C:11]([CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>N1C=CC=CC=1.C(O)C>[N:2](=[C:11]([CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CC(Cc1ccccc1)=NO
Yield: 29.8 %

Procedure:
A mixture of hydroxylamine hydrochloride (9 g.) and a solution of 1-phenyl-3-phthalimidoacetone (23.4 g.) in pyridine/ethanol (80 ml.-80 ml.) was stirred at ambient temperature for 3 days. The resulting solution was concentrated, the residue washed twice with a mixture of toluene and methylene chloride and dried. The residue was purified by column chromatography on activated silica gel using cyclohexane/EtOAc 7:3 v/v as eluant to give 2-oximino-1-phenyl-3-phthalimidopropane (7.35 g.) as a mixture of syn and anti isomers.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH:16]([CH:18](C(O)=O)[C:19]([OH:21])=[O:20])[CH3:17])=[CH:11][C:10]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)COCCO.COC.C(OC(C)C)(C)C.Cl>O>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH:16]([CH3:17])[CH2:18][C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)c1ccc(NCc2ccccc2)c(O)c1)C(C(=O)O)C(=O)O
Agent: COC
Agent: Cl
Solvent: O
Solvent: OCCOCCO
Solvent: CC(C)OC(C)C
Product: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c(O)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
78.9 g (220.8 mmol) 2-[2-(4-benzylamino-3-hydroxy-phenyl)-1-methyl-2-oxo-ethyl]-malonic acid are combined with 200 ml diethyleneglycol-dimethylether and stirred for 3 h at 140° C. The mixture is combined with water and diisopropylether, then it is adjusted with 6N hydrochloric acid to pH=2 and extracted with DCM. The org. phase is separated off and dried on magnesium sulphate, then the solv. is eliminated by rotary evaporation i.V., the residue is stirred with diisopropylether and filtered off.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[CH:5][N:6]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1>[CH2:23]([NH:25][C:26]([NH:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[C:7]([C:4]3[S:3][C:2]([CH3:1])=[N:6][CH:5]=3)[N:12]2[N:13]=1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: Cc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)s1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(C)s3)n2n1
Temperature: 125 °C

Procedure:
A suspension of the product of Step 1 (160 mg, 0.52 mmol), ethylisocyanate (205 μL, 2.6 mmol), and dibutyltin diacetate (5 drops) in dry toluene (6 mL) was heated at 125° C. in a microwave reactor for 1 h. After being cooled at room temperature the precipitated solid was filtered and washed with chloroform. The crude product was purified by flash chromatography (gradient 0-2% methanol/chloroform) to give 1-ethyl-3-[5-(2-methyl-thiazol-5-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea as a solid. MS m/z 380 (M+H+).
Reaction SMILES: C1CC(C(O)=O)NCC1.C(C1C=CN=CC=1)CC.C(C1C=C[N+]([O-])=CC=1)CC.OO.C(C1C=C(CCC)C=CN=1)#N.[CH2:42]([C:45]1[CH:50]=[CH:49][N:48]=[C:47]([C:51](=O)[CH2:52][CH2:53][CH2:54]C)[CH:46]=1)[CH2:43][CH3:44].C([Mg]I)CCC>C(O)(=O)C>[CH2:42]([C:45]1[CH:50]=[CH:49][N:48]=[C:47]([CH2:51][CH2:52][CH2:53][CH3:54])[CH:46]=1)[CH2:43][CH3:44]
Reactant: CCCCC(=O)c1cc(CCC)ccn1
Agent: CCCC[Mg]I
Agent: CCCc1cc[n+]([O-])cc1
Agent: CCCc1ccnc(C#N)c1
Solvent: CC(=O)O
Product: CCCCc1cc(CCC)ccn1

Procedure:
4-n-propyl-pyridine was prepared by alkylation of 4-picoline with sodium amide suspended in liquid ammonia and ethyl iodide, as described in Vogel's Textbook of Practical Organic Chemistry, Fourth Edition, p 903. It was obtained in good yield (77%). 2-cyano-4-n-propyl-pyridine was obtained from 4-n-propyl-pyridine following the procedure described by Shuman et al. [An Improved Synthesis of Homoproline and Derivatives Robert T. Shuman, Paul L. Ornstein, Jonathan W. Paschal, and Paul D. Gesellchen, J. Org. Chem. 1990, 55, 738-741]. In a first step, 4-n-propyl-pyridine (1 eq.) was converted into 4-n-propyl-pyridine N-oxide in glacial acetic acid, 30% hydrogen peroxide (1 eq.). Then, 4-n-propyl-pyridine N-oxide was converted into 2-cyano-4-n-propyl-pyridine in good yield (72%) with a modification of the Reissert-Henze reaction, reported by Fife [Fife, W. K. J. Org. Chem. 1983, 48, 1375.] 1-(4-propylpyridine-2-yl)pentan-1-one was obtained by treating the pyridyl cyanide with a small excess of the corresponding butyl magnesium iodide, as described by Teague et al. [Some Pyridylhydantoins P. C. Teague; A. R. Ballentine, G. L. Rushton J. Am. Chem. Soc 1953, 75, 3429-3430]. The ketone was separated from the reaction mixtures by extraction with chloroform, and obtained in relatively good yield (60%). 4-n-propyl-2-butyl-pyridine was obtained in high yield (85%) by a modified Wolff-Kishner reduction, as described by Huang-Minlon [A Simple Modification of the Wolff-Kishner Reduction, Huang-Minlon J. Am. Chem. Soc 1946, 68, 2487-2488].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[NH2:38]>>[Cl:34][C:35]1[CH:36]=[C:37]([NH:38][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN(C)CCOc1ccc(N)cc1Cl
Product: CN(C)CCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo-[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-chloro-4-{[2-(dimethylamino)ethyl]oxy}aniline in a manner analogous to Example 125. 1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.53 (s, 1H), 8.84 (d, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.58 (m, 1H), 7.53-7.44 (m, 3H), 7.34 (d, 1H), 7.24 (m, 2H), 7.12 (m, 1H), 7.05 (d, 1H), 4.08 (m, 2H), 2.66 (m, 2H), 2.25 (s, 6H); HRMS: calc. C34H29N7O2F2Cl (M+H)+ 640.2039 found 640.2047.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[OH:6])(=[O:3])[CH3:2].S([O-])([O-])(=O)=O.[Ca+2]>C(OCC)(=O)C.C(#N)C.C(O)C1C=CC=CC=1>[C:1]([C:4]1[C:5](=[O:6])[CH:7]=[CH:8][C:9](=[O:11])[C:10]=1[O:3][CH2:1][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: OCc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)C1=C(OCc2ccccc2)C(=O)C=CC1=O
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 4 g of 2-acetyl hydroquinone (I) in 90 ml of ethyl acetate, 100 ml of acetonitrile and 5 ml of benzyl alcohol (III) are added 60 g of crushed calcium sulfate oven dried at 240° C., then 8.5 g of powdered cuprous chloride. It is agitated in gaseous oxygen (at a pressure of one atmosphere) for two hours and thirty minutes at ambient temperature. Then it is diluted with toluene, filtered, the filtrate is evaporated, the residue taken up in a mixture of 120 ml of ether and 80 ml of cyclohexane; by trituration of the resulting mixture followed by a filtration separation of the insoluble matter, a solution is obtained which leads to the expected compound (Yield≃70%) after evaporation of the solvents.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[CH:19]=[CH:20]OCC.C(O)(C(F)(F)F)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([O:45][CH2:46][CH:47]([NH2:51])[CH:48]([CH3:50])[CH3:49])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH2:41][CH:42]([O:45][CH2:46][CH:47]([N:51]2[CH2:20][CH2:19][C:5]3[C:4](=[CH:9][C:8]([O:10][C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[F:18])=[CH:7][CH:6]=3)[C:3]2=[O:24])[CH:48]([CH3:49])[CH3:50])[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)C(N)COC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC=Cc1ccc(Oc2ccc(F)cc2F)cc1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C(COC1CCN(C(=O)OC(C)(C)C)CC1)N1CCc2ccc(Oc3ccc(F)cc3F)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To the solution of 5-(2,4-difluoro-phenoxy)-2-(2-ethoxy-vinyl)-benzoic acid methyl ester 9 (194 mg, 0.6 mmol) in dichloromethane (5 mL) was added 1 mL of TFA and five drops of water. The reaction was stirred at room temperature for ten minutes, at which time the solvent was removed. The reaction mixture was re-suspended in dichloroethane and 4-(2-amino-3-methyl-butoxy)-piperidine-1-carboxylic acid tert-butyl ester A11 (200 mg, 0.70 mmol), DIEA (154 mL, 0.87 mmol), and sodium triacetoxyborohydride (184 mg, 1.87 mmol) were added. The mixture was stirred at room temperature for fifteen minutes and then at 60° C. for additional 16 hours. The reaction was diluted with 100 mL CH2Cl2 and extracted with saturated brine (100 mL). The organic layer was concentrated and loaded onto a silica gel column and eluted with 2% methanol in dichloromethane to give 250 mg (79%) of 4-{2-[7-(2,4-difluoro-phenoxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-butoxy}-piperidine-1-carboxylic acid tert-butyl ester 15 as light yellow solid. TLC, Rf=0.3 (2% MeOH CH2Cl2). 1H NMR (CDCl3) δ 0.92 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.5 Hz, 3H), 1.31 (m, 1H), 1.44 (s, 9H), 1.61 (m, 2H), 2.2 (m, 1H), 2.90 (m, 2H), 3.14 (m, 2H), 3.41(m, 1H), 3.51 (m, 1H), 3.73 (m, 1H), 2.63 (m, 4H), 4.02 (m, 1H), 4.56 (m, 1H), 6,84 (m, 1H), 6.93 (m, 1H), 7.06 (m, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.54 (d, J=2.6 Hz, 1H), M+1 found 545.3; C30H38F2N2O5 requires 544.27.