Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:28])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.00 g (8.59 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 15b) in 20 mL of DCM and 20 mL THF is added 0.81 mL (8.59 mmol) phosphorus tribromide at 0° C. The cooling bath is removed and the mixture is stirred 1 h at RT in an ultrasound bath.
Reaction SMILES: [C:1]1(=[CH:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1([CH3:22])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[O:11]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:9][C:10]1([CH3:22])[C:14]([CH3:15])([CH3:16])[O:13][B:12]([C:17]2[CH:21]=[N:20][N:19]([C:1]3([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=2)[O:11]1
Reactant: N#CC=C1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C3(CC#N)CCCC3)c2)OC1(C)C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A mixture of cyclopentylideneacetonitrile (0.65 g, 0.0061 mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.60 g, 0.0031 mol, Aldrich, Cat. 525057), and 1,8-diazabicyclo[5.4.0]undec-7-ene (47 mg, 0.00031 mol, Aldrich, Cat. No. 139009) in acetonitrile (7 mL) was stirred at 60° C. overnight. After cooling to r.t., the reaction mixture was concentrated. The crude residue was purified by flash column chromatography on a silica gel column using 40% ethyl acetate in hexane as eluent to afford the desired compound (161 mg, 17.29%). LCMS (M+H)+: m/z=302.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21].C1COCC1>[Cu]I.CCOCC>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Ic1ccc(N2CCCC2)cc1
Reactant: C#CCOCCCCBr
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: BrCCCCOCC#Cc1ccc(N2CCCC2)cc1
Yield: 10.7 %

Procedure:
A mixture of 1-(4-iodophenyl)pyrrolidine (22.8 g), the product of stage (i) (16.0 g), BTPC (1.5 g) and copper (I) iodide (150 mg) in DEA (125 ml) and THF (125 ml) was stirred under nitrogen for 18 h. The dark mixture was treated with ether (250 ml), the precipitate was removed by filtration and the filtrate was concentrated to a black oil which was purified by FCC (hexane→System D 9:1) to give the title compound as a pale yellow oil (3.0 g) T.l.c. (System D 9:1) Rf 0.24.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[C:17]1([CH:23]2[CH2:25][O:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C)C>O1CCOCC1>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][C:2]([NH:1][CH2:25][CH:23]([OH:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])(=[O:11])[NH2:12]
Reactant: CC(C)(N)COc1ccc(O)c(C(N)=O)c1
Reactant: c1ccc(C2CO2)cc1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)NCC(O)c1ccccc1

Procedure:
A solution of 4.5 g of 5-(2-amino-2-methyl-propoxy)-salicylamide and 3.1 g of 2-phenyloxirane in 40 ml of dioxane is refluxed for 16 hours. The solvent is subsequently evaporated off under reduced pressure, and the residue is dissolved in 20 ml of 2N hydrochloric acid, and extracted with 50 ml of ether. The water phase is separated; it is rendered alkaline with concentrated ammonia, and the liberated base is extracted with 200 ml of ethyl acetate. Customary further processing yields a light-coloured foam, from which is obtained, by recrystallisation from isopropanol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1,1-dimethyl-ethyl]-aminomethyl]-benzyl alcohol, m.p. 121°-123°. It forms a neutral fumarate, m.p. 209°-210° (from methanol).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([N:4]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCBr
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 2.12 g of 2-(trimethylsilyl)ethyl 3-(cyclopropylsulfamoyl)benzoate, 1.45 g of ethyl 4-bromobutyrate, 2.57 g of potassium carbonate, and 21 mL of DMF was stirred at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.48 g of 2-(trimethylsilyl)ethyl 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoate as a colorless oily substance. ESI+: 456
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2Br)[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:38]([O:43]C)([O:41][CH3:42])[O:39][CH3:40]>>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[P:38]([O:41][CH3:42])([O:39][CH3:40])=[O:43])[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COP(OC)OC
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CCC12
Product: COP(=O)(OC)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Yield: 25 %

Procedure:
A solution of 3-bromo-7-[(phenoxyacetyl)amino]-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (1.12 g, 2 mmol) in trimethyl phosphite (5 mL) was refluxed under nitrogen for two hours. After cooling, the reaction was poured into hexanes. The supernatant was removed and the residue purified by flash chromatography on silica gel (50% ethyl acetate/hexanes to 100% ethyl acetate) to provide 7-[(phenoxyacetyl)amino]-8-oxo-3-(dimethoxyphosphinyl)-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (300 mg; 25%):
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH:34]([OH:36])[CH3:35])N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:2][N:3]([CH2:33][CH:34]([OH:36])[CH3:35])[C:4]=2[C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[CH:12][CH:11]=1
Reactant: CC(O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(O)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=6.2 Hz, 2H), 8.23 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (m, 2H), 7.75 (m 2H), 7.57 (t, J=6.6 Hz, 1H), 7.20 (d, J=9.1 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H) 7.00 (dd, J=6.2, 1.7 Hz, 2H), 5.42 (s, 2H), 4.17 (m, 1H), 3.94 (m, 2H), 3.86 (m, 1H), 1.12 (d, J=6.6 Hz, 3H); MS: (M+H m/z=437.3).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([F:29])=[CH:10][C:11]3[C:12]([CH:28]=2)=[N:13][C:14]2[N:15]([CH3:27])[CH:16]=[C:17]([C:22]([O:24]CC)=[O:23])[C:18](=[O:21])[C:19]=2[CH:20]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:31][CH3:32].[H-].[Na+]>CN(C)C=O>[CH:1]1([N:7]([CH2:31][CH3:32])[C:8]2[C:9]([F:29])=[CH:10][C:11]3[C:12]([CH:28]=2)=[N:13][C:14]2[N:15]([CH3:27])[CH:16]=[C:17]([C:22]([OH:24])=[O:23])[C:18](=[O:21])[C:19]=2[CH:20]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(NC4CCCCC4)c(F)cc3cc2c1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C)C1CCCCC1

Procedure:
8-[(Cyclohexyl)(ethyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared from 0.5 g of ethyl 8-cyclohexylamino-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate, 0.19 cm3 of iodoethane, 0.096 g of sodium hydride as a 60% dispersion in mineral oil and 10 cm3 of dimethylformamide. After treatment with 10 cm3 of water and 2 cm3 of 1N hydrochloric acid, the mixture was extracted 3 times with 20 cm3 of trichloromethane. The combined organic phases were washed 1 time with 20 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at a temperature around 40° C. 0.25 g of 8-[(cyclohexyl)(ethyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was obtained in the form of a yellow solid melting at about 230° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH2:16][CH3:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)=O.[C:18]1([CH:24](P([O-])(OCC)OCC)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:18]1([C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:1][C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:16][CH3:17])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCO[PH]([O-])(OCC)C(c1ccccc1)c1ccccc1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C=C(c3ccccc3)c3ccccc3)ccc21
Yield: 87.3 %

Procedure:
25.3 g (111.7 mmol) of 3-formyl-9-ethylcarbazole (2') (manufactured by Tokyo Kasei Kogyo Co.), 39.6 g (122.9 mmol) of diethyl diphenylmethylphosphite, 253 ml of DMF and 15.04 g (134.0 mmol) of potassium-t-butoxide were allowed to react and after treated in the same manner as with Example 1 (2) to obtain 36.44 g of 3-(2',2'-diphenylvinyl)-9-ethylcarbazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[SH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([S:12][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=[CH:10][N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: Sc1nccn1-c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CSc2nccn2-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A mixture consisting of 5.1 g of 1-(2-pyridyl)imidazole-2-thiol, 5.2 g of anhydrous potassium carbonate, 3.7 g of benzyl chloride and 50 ml of acetonitrile was stirred at room temperature for 4 hours. After completion of the reaction, solids were filtered off and the filtrate was concentrated under reduced pressure. Crystals precipitated were collected by filtration to give 7.1 g of 2-benzylthio-1-(2-pyridyl)imidazole (m.p.: 76° to 77° C.). To a mixture consisting of 7.1 g of the thus obtained crystals, 50 ml of methylene chloride, 50 ml of water and 22 g of conc. hydrochloric acid was added dropwise 80 g of 6% sodium hypochlorite solution under vigorous stirring at -10° to 0° C. over 1 hour. After completion of the dropwise addition, the resulting mixture was stirred at the same temperature for 30 minutes. Then, the organic layer was separated and the aqueous layer was extracted with methylene chloride. After the organic layers were combined and washed with water, to the organic layer was added dropwise 10 ml of a 28% aqueous ammonia under ice-cooling while vigorous stirring. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness and the thus obtained concentrated residue was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give 3.0 g of a crude product of the desired compound. Crystals precipitated from the resulting crude product were collected by filtration to give 0.8 g of the desired compound. m.p.: 187° to 188° C.
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])[NH2:2].[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[O:14][CH2:15][CH2:16][OH:17])[CH:10]=[CH:9][N:8]=[CH:7]1.Cl>C(#N)C>[ClH:5].[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[O:14][CH2:15][CH2:16][O:17][S:1](=[O:4])(=[O:3])[NH2:2])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1cccc(-n2ccnc2)c1
Agent: Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
A solution of sulfamoyl chloride (0.0275 mole) in 60 ml of acetonitrile was treated dropwise with a solution of 5.1 g (0.025 mole) of 2-[3-(1H-imidazol-1-yl)phenoxy]ethanol in 100 ml of acetonitrile. The mixture was stirred at ambient temperature under nitrogen for 20 hr. The mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and dilute potassium carbonate solution. The organic fraction was again concentrated under vacuum to a crystalline residue. This residue was dissolved in warm 95% ethanol and treated with 1 equivalent of anhydrous hydrogen chloride. The solution was chilled and the precipitate was collected and dried to give 4.0 g (50%) of the title compound as a pink powder, mp 149.0°-150.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:29])[CH2:27][CH3:28]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:26][CH2:27][CH3:28])=[O:20]
Reactant: CCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: CCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), propylamine (0.190 g, 3.21 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 6 hours at room temperature. After completion of the reaction, the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.360 g, 30.9% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([OH:19])[C:14](=[NH:18])[O:15]CC.O1CCCC1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:19][C:1](=[O:2])[NH:15][C:14]1=[O:18]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2F)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 2 hours at room temperature was employed following the phosgene perfusion step, ethyl 1-(2-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (14.5 g., 0.062 mole) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2fluorophenyl)oxazolidine-2,4-dione (7.32 g., 60%; m.p. 129°-131° C.).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][CH3:11].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.O>C1COCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH:10]([CH3:11])[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the LDA solution at -78° C., was added dropwise a solution of 5 mL (44 mmoles) of ethyl propionate in 20 mL of THF. Stirring was continued at —78° C. for 1 hour, after which a solution of 10 g (40 mmoles) of p-bromo benzylbromide in 25 mL of THF was added dropwise. Stirring was continued at −78° C. for 2 hours. Water was then added dropwise and the reaction was allowed to warm to room temperature.
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[CH:21]4)=[N:15][N:16]=2)[N:13]=1>CO>[CH3:1][O:2][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[CH:21]4)=[N:15][N:16]=2)[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Agent: [K+]
Solvent: CO
Product: COc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 130 °C

Procedure:
To a 5 ml microwave vial 1 ml of methanol was added followed by 15 mg of potassium carbonate, and 25 mg (0.067 mmol) of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoline. The reaction mixture was heated for 3800 seconds at 130° C. in a microwave. The reaction mixture was then filtered and purified by preparatory HPLC to return the title compound (11.6 mg, 47%). Analytical data is presented in Table 2.
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>N1C=CC=CC=1>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:4]2[N:3]=1)=[O:33])[CH3:30]
Reactant: CCN=C=O
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A mixture of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (304 mg, 0.805 mmol), ethyl isocyanate (314 μL, 3.98 mmol) and pyridine (10 mL) was stirred at 50° C. for 18 hr. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→O/100) and recrystallized from ethyl acetate-hexane to give the title compound (151 mg, 42%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[C:22](Cl)=[CH:21][C:20]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:19][C:18]=23)=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:31][O-:32].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([O:32][CH3:31])=[CH:21][C:20]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:19][C:18]=23)=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(Cl)cc(-c4ccc(Cl)cc4)nc23)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared by stirring 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(3-methanesulfonyl-phenyl)-amide (example 175) (46 mg) with a solution of sodium methoxide (11 mg) in methanol (1.5 mL) for 2 h at 50° C., followed by precipitation of the product by the addition of water (10 mL). Pale-yellow solid. MS (ISP) 457.5 [(M+H)+]; mp 265° C.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1>>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Sc1ncnc2ccccc12
Reactant: ClCc1ccco1
Product: c1coc(CSc2ncnc3ccccc23)c1
Yield: 49.4 %

Procedure:
The title compound(3.69 g) was prepared from 4-mercaptoquinazoline(5.0 g) and 2-chloromethylfuran(5.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1c(F)ccc(N)c1Nc1ccccc1
Temperature: 90 °C
Yield: 87.9 %

Procedure:
To a mixture of (3-fluoro-2-methyl-6-nitrophenyl)phenylamine (1.5 g, 6.1 mmol) in a 3:1 mixture of MeOH:water (40 mL) were added NH4Cl (1.88 g, 36.5 mmol) and iron powder (1.36 g, 24.4 mmol) and the reaction mixture heated at 90° C. for 1 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a pink solid (1.16 g, 88%). 1H NMR (CDCl3, 400 MHz): δ 7.22-7.15 (2H, m), 6.88-6.77 (2H, m), 6.64-6.55 (3H, m), 5.03 (1H, br s), 3.68 (2H, br s), 2.11 (3H, d, J=2.24 Hz).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1.Cl.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=[S:17])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(c2cccc(Br)n2)COCC(=O)N1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(c2cccc(Br)n2)COCC(=S)N1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholin-3-one (4.65 g, 17.15 mmol) and P2S5 (4.57 g, 20.58 mmol) in pyridine (60 ml) was stirred at 80° C. under N2 for 6 h. The reaction mixture was cooled to rt and diluted with 0.5N aq. HCl and EtOAc. The phases were separated and the aq. phase was twice extracted with EtOAc. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was obtained as a pale yellow solid after flash chromatography on silica gel (cyclohexane/EtOAc 100:0 to 75:25). HPLC RtH4=0.89 min; ESIMS: 287, 289 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 7.86-7.82 (m, 1H), 7.61 (dd, 1H), 7.39 (dd, 1H), 4.44-4.34 (d, 2H), 4.13 (d, 1H), 3.74 (d, 1H), 1.52 (s, 3H).