Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].CC(S([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:24][N:23]=1)(=O)=O)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])=[CH:24][N:23]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)S(=O)(=O)c1ccc(S(=O)(=O)C(C)C)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Yield: 42 %

Procedure:
To 4.89 g of 3,4-dichlorophenol dissolved in a 25 ml THF/25 ml DMSO mixture was added 3.2 g of t-BuOK and then 8.74 g of 2,5-bis((1-methylethyl)sulfonyl)pyridine, and the resulting mixture was heated at 58° C. for 11/2 hrs. The reaction mixture was allowed to cool overnight and then poured in approximately 3 to 4 volumes of water and stirred. The yellow-white precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the product, 2-(3,4-dichlorophenoxy)-5-((1-methylethyl)sulfonyl)pyridine, (42% yield), as tiny white needles, m.p. 91°-92° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([Cl:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Product: O=C(Cl)COc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (4-nitrophenoxy)acetic acid (50 g) and thionyl chloride (150 ml) was heated under reflux for 3 h. The solution was concentrated and then coevaporated with benzene to give 4-nitrophenoxyacetyl chloride as a solid. A solution of this solid (9.4 g) in acetone (100 ml) was added dropwise to a stirred mixture of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (10 g) and sodium hydrogen carbonate (9 g) in acetone (100 ml) at 0°. Stirring was continued at room temperature for 16 h, the mixture was then filtered, and the filtrate was concentrated. The residue was treated with water and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated to give the title compound (6.6 g) as an oil.
Reaction SMILES: [CH:1](/[S:9](Cl)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH:1](/[S:9]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([Cl:13])=[CH:15][CH:16]=1)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(Cl)cc1
Yield: 56 %

Procedure:
A solution of (E)-styrylsulfonyl chloride (10 mmol) and 4-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 107-109° C. was obtained in 56% yield.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH:13]1[F:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][S:27]([O:18][CH:15]1[CH2:16][CH2:17][CH:12]([O:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]([F:19])[CH2:14]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)[Si](C)(C)OC(COC1CCC(O)CC1F)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(COC1CCC(OS(C)(=O)=O)CC1F)c1ccccc1
Reaction time: 0.02 h
Yield: 95.5 %

Procedure:
To a solution of 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexanol (8.46 g, 22.9 mmol) in dichloromethane (100 mL) at 0° C. was added methanesulfonyl chloride (2.49 mL, 32.1 mmol) and diisopropylethylamine (11.1 mL, 64.1 mmol). The reaction mixture was stirred for 1 min, diluted with dichloromethane and washed with 5% potassium bisulfate. The layers were separated and the aqueous extracted with dichloromethane (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (hexane: ethyl acetate 70:30) gave 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexyl methanesulfonate (9.77 g, 100% yield) as a clear oil.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][OH:16])[CH2:10]1>>[OH:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][N:9]([C:3]2[S:4][CH2:5][C:6](=[O:8])[N:7]=2)[CH2:10]1
Reactant: OCC1CNCCO1
Reactant: CSC1=NC(=O)CS1
Product: O=C1CSC(N2CCOC(CO)C2)=N1

Procedure:
2-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and Morpholin-2-yl-methanol following general procedure E.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].[OH-].[K+]>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:10]=[C:4]([F:3])[C:5]([NH2:6])=[C:7]([F:11])[CH:8]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F
Yield: 78.5 %

Procedure:
300 g of bromine was added drop-wise to 231 g of 2,6-difluoroaniline dissolved in 400 ml of chloroform. The mixture was refluxed for one hour and the reaction solution was poured into an aqueous 10% solution of potassium hydroxide. The potassium hydroxide was extracted with chloroform and the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water. The chloroform was distilled off and the residue was distilled under reduced pressure (bp: 70°-80° C./4 mmHg) and recrystallized from hexane, to yield 292 g of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10](=O)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O>[CH2:1]([O:3][C:4]1[C:9]2[C:10](=[N:20][OH:21])[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2c1C(=O)CO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cccc2c1C(=NO)CO2
Temperature: 23 °C
Yield: 93 %

Procedure:
A mixture of 4-ethoxy-benzofuran-3-one (CAS no: 7169-36-0) (4.18 g, 23.5 mmol), sodium acetate (3.96 g, 48.3 mmol) and hydroxylamine hydrochloride (3.34 g, 48.1 mmol) in ethanol (30 mL) was refluxed for 16 h. Cooled to 23° C., diluted with water (50 mL), filtered the precipitate off, washed with water, ethanol and diethyl ether and dried in high vacuum to give the title compound as a white solid (4.2 g, 93%); MS: m/e=194.3 (M+H+).
Reaction SMILES: [H-].[Na+].C[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20]C)([CH3:13])[CH3:12].CCOCC>CN(C)C=O>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([CH3:13])[CH3:12]
Reactant: COc1ccccc1C(C)(C)c1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(c1ccccc1O)c1ccccc1O
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Sodium hydride (2.60 g of 60 percent dispersion in oil) was placed in a 1 l flask and extracted twice with pentane. To this was added first 250 ml of dimethylformamide and then, dropwise with stirring over 1 hour, 6.0 ml of ethanethiol in 40 ml of dimethylformamide. 2,2-Bis(2-methoxyphenyl)propane (8.0 g, 31 mmol) in 100 ml of dimethylformamide was then added and the mixture was heated at reflux with stirring for 24 hours and allowed to stand at ambient temperature for another approximately 18 hours. One 1 of ether was added and the resulting solution was extracted with water and twice with 4.0N sodium hydroxide solution. The combined aqueous extracts were neutralized with concentrated hydrochloric acid to a pH of about 9-10. Ether (500 ml) was then added and, after shaking, the ether layer was separated, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 3 g of the title compound as a brown oil containing some dimethylformamide. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].N12CCCN=C1CCCCC2>>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:15][CH2:14][C:13]([F:17])([F:16])[F:12]
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(C(=O)O)nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(=O)O)nc1OCC(F)(F)F
Temperature: 150 °C
Reaction time: 120 h
Yield: 72 %

Procedure:
A mixture of 6-chloro-5-methyl-pyridine-2-carboxylic acid (CAN 1166828-13-2, 200 mg, 1.17 mmol), 2,2,2-trifluoroethanol (466 mg, 336 μl, 4.66 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (CAN 83329-50-4, 887 mg, 870 μl, 5.83 mmol) was shaken in a sealed tube for 2 days at 140° C. and subsequently for additional 5 days at 150° C. The brown solution was poured into 25 mL ice/0.1 N HCl and extracted with i-PrOAc (2×25 mL). The organic layers were washed with ice/brine (2×25 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (198 mg, 58%) as off-white solid containing traces of starting material, MS (EI): m/e=233.9 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.C(C#N)(C)=[O:23].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>O>[OH:23][C:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15]
Reactant: CC(=O)C#N
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCO)O2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCO)=C(C)C1=O
Temperature: 0 °C

Procedure:
6-Hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide (2.38 g, 8.11 mmol) was dissolved into 150 mL AcCN, cooled to 0° C. and treated with 9.75 g CAN (17.84 mmol) in 30 mL H2O over 20 minutes. EtOAc (150 mL) and H2O (20 mL) were then added, layers separated and the organic phase washed 21×20 mL H2O. The aqueous phase was back extracted 4×50 mL EtOAc and the combined organics washed with saturated NaCl, dried over Na2SO4 and concentrated to a yellow powder. Flash chromatography yielded 1.68 g of 2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][N:5]1[C:13]2[CH2:12][C:11]([CH3:15])([CH3:14])[CH:10]([CH:16]=O)[C:9](=O)[C:8]=2[CH:7]=[N:6]1>CO>[CH3:1][N:2]1[CH:16]=[C:10]2[C:11]([CH3:15])([CH3:14])[CH2:12][C:13]3[N:5]([CH3:4])[N:6]=[CH:7][C:8]=3[C:9]2=[N:3]1
Reactant: CNN
Reactant: Cn1ncc2c1CC(C)(C)C(C=O)C2=O
Solvent: CO
Product: Cn1cc2c(n1)-c1cnn(C)c1CC2(C)C
Temperature: 0 °C

Procedure:
A solution of 0.59 ml of methylhydrazine in 20 ml of methanol was added dropwise to an ice-cold solution of 2.2 g of 4,5,6,7-tetrahydro-1,6,6-trimethyl-4-oxo-1H-indazole-5-carboxaldehyde in 80 ml of methanol. The solution was heated at reflux for 45 minutes and the solvent was removed under reduced pressure. The residue was dissolved in hot toluene and cooled to provide off-white crystals which were recrystallized from toluene to give 2,4,5,6-tetrahydro-2,4,4,6-tetramethylbenzo[1,2-c:3,4-c']dipyrazole melting at about 172°-173° C. The initial toluene mother liquor was concentrated under reduced pressure to provide tan crystals which were recrystallized from toluene to give 1,4,5,6-tetrahydro-1,4,4,6-tetramethylbenzo[1,2-c:3,4-c']dipyrazole melting at about 105°-108° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C:14]1([CH3:20])[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>CCC(C)=O.ClCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][NH:15][C:14]([CH3:20])([CH3:13])[CH2:19]2)=[N:3][N:4]=1
Reactant: CC1(C)CNCCN1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC1(C)CN(c2nnc(Cl)c3ccccc23)CCN1
Temperature: 25 °C

Procedure:
1,4-dichlorophthalazine (1 g, 5 mmol) and 2,2-dimethyl piperazine (1.75 g, 15 mmol, 3 eq) were slurried in 5 mL of MEK for 3 h at 45° C. After cooling to rt, the reaction was diluted with 150 mL of dichloromethane and washed with 1×20 mL of sat. NaHCO3 and 1×20 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (100:5→8:1 dichloromethane:methanol:triethylamine) afforded 1-chloro-4-(3,3-dimethylpiperazin-1-yl)phthalazine. MS (M+H)+=277.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:18][CH2:19][CH2:20][CH2:21]Br.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Reactant: BrCCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1oc2cccc(N3CCCC3)c2c1C
Temperature: 110 °C
Yield: 48 %

Procedure:
To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq., prepared according to Example 60, Step 1) were added toluene (3 mL), 1,4-dibromobutane(272 uL, 2.28 mmol, 1 eq.), and N,N-diisopropylethylamine (953 uL, 5.47 mmol, 2.4 eq.) under argon in a sealed tube and the mixture was heated at 110° C. for 16 hours. After work-up and flash column chromatography, 3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carboxylic acid ethyl ester was obtained in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 1.9 (m, 4 H) 2.7 (s, 3 H) 3.1 (m, 4 H) 4.3 (q, J=7.1 Hz, 2 H) 6.8 (dd, J=8.0, 0.6 Hz, 1 H) 7.2 (dd, J=8.3, 0.8 Hz, 1 H) 7.3 (m, 1 H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:15])(=[O:14])[CH2:12][CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:11]([O:15][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COC(=O)CC

Procedure:
A solution of 71 ml of ethyl 4-chloro-3-oxobutyrate in 165 ml of toluene is added to a boiling solution of 73 ml of propionic acid and 132 ml of triethylamine in 833 ml of toluene in the course of 30 minutes. The mixture is boiled under reflux for 90 minutes and then cooled, the triethylamine hydrochloride which has precipitated out is filtered off with suction and extracted twice with 300 ml of water each time and the solvent is distilled off in vacuo. The residue is subjected to fractional distillation under a high vacuum.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>[Cu](I)I.CN(C)C>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:19]#[C:20][C:3]1[C:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:2]=1
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: CN(C)C
Product: C[Si](C)(C)C#Cc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Thereafter, to 150 ml of trimethylamine were added 7.89 g of 2-iodofluorene, 379 mg (0.54 mmol) of bis[triphenylphosphine]palladium dichloride and 51 mg (0.27 mmol) of copper iodide. 4.2 ml (29.7 mmol) of trimethylsilylacetylene was added slowly to the reaction mixture. After the reaction was stirred for 8 h at room temperature, solvent was removed under reduced pressure. The residue was extracted with benzene and the benzene layer was washed with distilled water. The washed benzene layer was concentrated to give 6.02 g (85%) of 2-trimethylsilylethynyl fluorene.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=O.O>N1C=CC=CC=1>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([C:21]2[O:15][N:14]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[N:1]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(C/C(N)=N/O)c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 115 °C
Yield: 22.4 %

Procedure:
A solution of the compound (2.2 g) obtained in Example 114a in pyridine (40 mL) was cooled in an ice bath and 3-(trifluoromethyl)benzoyl chloride (4.16 g) was added. The reaction mixture was heated to 110-120° C. overnight, cooled to room temperature, and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed successively with 1N aqueous hydrochloric acid solution, and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-petroleum ether) to give the title compound (0.85 g) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:12][C@@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M-(CH2═CMe2)-CO2]H+ 236.3, no molecular ion.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[N:7]=1)C.[OH-].[Na+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>O.C1(C)C(C)=CC=CC=1>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[N:7]=1
Reactant: CN(C)Cc1ccc(O)c(Cl)n1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1ccc(Cc2ncc[nH]2)nc1Cl

Procedure:
This hydrochloride was dissolved in water and the solution was neutralised with dilute sodium hydroxide solution and evaporated. The residue was extracted several times with hot toluene and the combined extracts were filtered and evaporated to give the corresponding free base. The base (3.70 g) and imidazole (1.5 g) were heated under reflux in xylene (50 ml) for 3 hours. The mixture was then evaporated and the resulting dark residue was extracted several times with hot water. The aqueous solution was evaporated and the residue was crystallised first from ethyl acetate and then from water to give 2-(1-imidazolylmethyl)-5-hydroxy-6-chloropyridine (0.88 g), m.p. 157°-158°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH-].[K+]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2c(c1)OCCO2
Yield: 67.1 %

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carboxaldehyde (2.03 g, 12.4 mmol), was slurried in water (50 ml) at 80° C. Potassium permanganate (2.70 g, 17.1 mmol) as a solution in water (50 ml) was added over 1 hour. The mixture was then heated for a further 2 hours after which time the reaction mixture was basified with 10% aqueous potassium hydroxide. The resulting precipitate was removed by filtration and washed with water (2×50 ml). The combined filtrates were acidified with concentrated hydrochloric acid and the resulting solid isolated by filtration and dried under vacuum. This provided the desired compound as a white solid (1.50 g, 67%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][OH:9])[CH3:7])[CH3:5].C(O)(C)(C)C.CC([O-])(C)C.[K+].[CH3:21][O:22][N:23]([C:28]1[C:29](Cl)=[N:30][CH:31]=[CH:32][CH:33]=1)[C:24](=[O:27])[O:25][CH3:26]>CS(C)=O>[CH3:21][O:22][N:23]([C:28]1[C:29]([O:9][N:8]=[C:6]([CH3:7])[C:4](=[N:3][O:2][CH3:1])[CH3:5])=[N:30][CH:31]=[CH:32][CH:33]=1)[C:24](=[O:27])[O:25][CH3:26]
Reactant: CON=C(C)C(C)=NO
Reactant: COC(=O)N(OC)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: CON=C(C)C(C)=NOc1ncccc1N(OC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 70° C., a mixture of 1.2 g (9.2 mmol) of 2-methoxyimino-3-hydroxyiminobutane and 25 ml of tert-butanol was treated with 1.03 g (9.2 mmol) of potassium tert-butylate, and the mixture was stirred for 1 hour. The reaction mixture was freed from solvent under reduced pressure at approximately 40° C. The residue was introduced into 15 ml of dimethyl sulfoxide, and 2 g (9.2 mmol) of methyl N-methoxy-N-(2-chloropyridin-3-yl)carbamate, dissolved in 3 ml of dimethyl sulfoxide, were added at 50° C. The mixture was stirred for 2 hours at 100° C., and the reaction mixture was transferred to approximately 150 g of ice and extracted with tert-butyl methyl ether. The organic phases were combined, washed with water, dried, and the solvent was removed, under reduced pressure. The resulting residue was purified by column chromatography over silica gel using cyclohexane/ethyl acetate (2:1). This gave 470 mg (17%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl-].[NH4+:32]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:32][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=4[CH:17]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)[nH]2)cc1
Yield: 46.4 %

Procedure:
8.0 g (20 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) and 5.5 g (0.1 mole) of ammonium chloride in 150 ml of dry dimethylformamide were heated for 6 hours at 150° C. After cooling, the mixture was poured onto water and the precipitated crystals were filtered off under suction, washed several times with water and dried in a stream of nitrogen. Purification by column chromatography (silica gel; n-heptane plus increasing amounts of ethyl acetate) and recrystallization from ethanol gave 3.6 g of the title compound of melting point 76°-179° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:24])[CH2:29][CH2:28]1
Reactant: OC1CCNCC1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)N3CCC(O)CC3)ccc1OCC2

Procedure:
Following the procedure for 116, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-hydroxy piperidine to give 118 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1 Hz, 1H); 7.94 (s, 1H); 7.35 (dd, J=8.3, 2.1 Hz, 1H); 7.23 (d, J=8.3 Hz, 1H); 6.88 (s, 1H); 5.76-5.62 (m, 1H); 4.58 (t, J=5.8 Hz, 2H); 4.19 (br s, 1H); 4.07-3.98 (m, 1H); 3.82 (br s, 1H); 3.37 (br s, 2H); 3.20 (t, J=5.8 Hz, 2H); 1.95 (br s, 2H); 1.70 (d, J=3.9 Hz, 1H); 1.67-1.54 (d, J=6.6 Hz, 8H). LCMS: RT=8.77 min, M+H+=423